Articles de revues : « CXCR4 axi »

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Rini, Brian I., Bernard Escudier, Danielle Murphy, Panpan Wang, Jamal Christo Tarazi et Robert J. Motzer. « Angiogenic and immunomodulatory biomarkers in axitinib-treated patients (pts) with advanced renal cell carcinoma (aRCC). » Journal of Clinical Oncology 37, n^o 7_suppl (1 mars 2019) : 614. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.614.

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614 Background: Axitinib (axi) is approved for 2nd-line treatment of aRCC. In AXIS trial, median progression-free survival (PFS) was significantly longer in axi- vs sorafenib (sor)-treated pts (hazard ratio [HR] 0.67, 95% CI 0.54–0.81, P<0.0001). Association between mRNA/miRNA expression and clinical outcomes in a subset of axi- or sor-treated pts from AXIS was assessed. Methods: mRNA/miRNA analyses were performed on archival tumor samples. Expression was summarized for responders (complete and partial response) vs non-responders (stable and progressive disease), and for maximum percent tumor change. PFS and overall survival (OS) were analyzed by Kaplan-Meier. Results: Pt characteristics were similar between axi (n=34) and sor (n=33) arms. Association with outcomes is shown in the Table. A correlation was observed for CD68 protein and mRNA expression in axi-treated pts (R=0.4774 P=0.0043 and R=0.3985 P=0.0196, respectively). Both CXCR4 and TLR3 showed differences between treatment arms and association with PFS. TNFSF10 <median, and CD163, CSF1R and miR-221-5p ≥median were associated with shorter OS with axi vs sor ( P<0.05). Clinical trial information: NCT00678392. Conclusions: Immune-related biomarkers were associated with clinical outcomes in axi/sor-treated aRCC pts. Lower CCR7 expression was associated with better response and OS in axi-treated pts. CXCR4 and TLR3 may be predictive of response to axi. Analysis in a larger cohort is warranted.[Table: see text]

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Zheng, Lanzhi, Zhuoyi Zhang, Kang Song, Xiaoyang Xu, Yixin Tong, Jinling Wei et Lu Jiang. « Potential biomarkers for inflammatory response in acute lung injury ». Open Medicine 17, n^o 1 (1 janvier 2022) : 1066–76. http://dx.doi.org/10.1515/med-2022-0491.

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Abstract Acute lung injury (ALI) is a severe respiratory disorder occurring in critical care medicine, with high rates of mortality and morbidity. This study aims to screen the potential biomarkers for ALI. Microarray data of lung tissues from lung-specific geranylgeranyl pyrophosphate synthase large subunit 1 knockout and wild-type mice treated with lipopolysaccharide were downloaded. Differentially expressed genes (DEGs) between ALI and wild-type mice were screened. Functional analysis and the protein–protein interaction (PPI) modules were analyzed. Finally, a miRNA-transcription factor (TF)-target regulation network was constructed. Totally, 421 DEGs between ALI and wild-type mice were identified. The upregulated DEGs were mainly enriched in the peroxisome proliferator-activated receptor signaling pathway, and fatty acid metabolic process, while downregulated DEGs were related to cytokine–cytokine receptor interaction and regulation of cytokine production. Cxcl5, Cxcl9, Ccr5, and Cxcr4 were key nodes in the PPI network. In addition, three miRNAs (miR505, miR23A, and miR23B) and three TFs (PU1, CEBPA, and CEBPB) were key molecules in the miRNA-TF-target network. Nine genes including ADRA2A, P2RY12, ADORA1, CXCR1, and CXCR4 were predicted as potential druggable genes. As a conclusion, ADRA2A, P2RY12, ADORA1, CXCL5, CXCL9, CXCR1, and CXCR4 might be novel markers and potential druggable genes in ALI by regulating inflammatory response.

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Krikun, Graciela. « The CXL12/CXCR4/CXCR7 axis in female reproductive tract disease : Review ». American Journal of Reproductive Immunology 80, n^o 5 (14 août 2018) : e13028. http://dx.doi.org/10.1111/aji.13028.

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Yao, Miao-En, Yi Huang, Qing-Qing Dong, Yi Lu et Wei Chen. « The Renshen Chishao Decoction Could Ameliorate the Acute Lung Injury but Could Not Reduce the Neutrophil Extracellular Traps Formation ». Evidence-Based Complementary and Alternative Medicine 2022 (29 août 2022) : 1–16. http://dx.doi.org/10.1155/2022/7784148.

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The acute lung injury (ALI) causes severe pulmonary diseases, leading to a high mortality rate. The Renshen and Chishao have protective and anti-inflammatory effects against the ALI. To explore the protective effects of the Renshen Chishao (RC) decoction against the ALI, we established the lipopolysaccharide-indued ALI model and randomly divided the mice into seven groups: control group, ALI group, high-dose RC group, middle-dose RC group, low-dose RC group, middle-dose RC group + CXCR2 antagonist group, and ALI + CXCR2 antagonist group. We estimated the lung injury by the hematoxylin and eosin staining, the neutrophil extracellular traps (NETs) formations by the immunofluorescence colocalization and enzyme-linked immunosorbent assay (ELISA), and the CXCR2/CXCL2 pathway by the flow cytometry, ELISA, and real-time polymerase chain reaction. We conducted the high-throughput sequencing and enrichment analyses to explore the potential mechanisms. The results showed that the RC decoction pathologically ameliorated the lipopolysaccharide-induced lung injury and inflammatory response but failed to reduce the circulating and lung tissue NETs formation and the blood neutrophil percent. The high-dose RC decoction increased the plasma CXCL2 level, but the RC decoction had no effects on the neutrophilic CXCR2 levels. Under the inhibition of the CXCR2, the middle-dose RC decoction still decreased the lung injury score but as yet had unobvious influence on the NETs formation. Other potential mechanisms of the RC decoction against the ALI involved the pathways of ribosome and coronavirus disease 2019 (COVID-19); the target genes of inflammatory factors, such as Ccl17, Cxcl17, Cd163, Cxcr5, and Il31ra, and lncRNAs; and the regulations of the respiratory cilia. In conclusion, the RC decoction pathologically ameliorated the lipopolysaccharide-induced lung inflammatory injury via upregulating the CXCL2/CXCR2 pathway but could not reduce the circulating or lung tissue NETs formation.

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Liu, Nanmei, Andreas Patzak et Jinyuan Zhang. « CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury ». American Journal of Physiology-Renal Physiology 305, n^o 7 (1 octobre 2013) : F1064—F1073. http://dx.doi.org/10.1152/ajprenal.00178.2013.

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Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) can repair acute kidney injury (AKI), but with limited effect. We test the hypothesis that CXCR4 overexpression improves the repair ability of BMSCs and that this is related to increased homing of BMSCs and increased release of cytokines. Hypoxia/reoxygenation-pretreated renal tubular epithelial cells (HR-RTECs) were used. BMSCs, null-BMSCs, and CXCR4-BMSCs were cocultured with HR-RTECs. The number of migrating BMSCs was counted. Proliferating cell nuclear antigen (PCNA) expression, cell death, and expressions of cleaved caspase-3 and Bcl-2 in cocultured HR-RTECs were measured. Cytokeratin 18 (CK18) expression and cytokine secretions of the BMSCs cultured with HR-RTEC supernatant were detected. BMSC homing, renal function, proliferation, and cell death of tubular cells were assayed in the AKI mouse model. CXCR4-BMSCs showed a remarkable expression of CXCR4. Stromal cell-derived factor-1 in the HR-RTEC supernatant was increased. Migration of BMSCs was CXCR4-dependent. Proportions of CK18+ cells in BMSCs, null-BMSCs, and CXCR4-BMSCs showed no difference. However, CXCR4 overexpression in BMSCs stimulated secretion of bone morphogenetic protein-7, hepatocyte growth factor, and interleukin 10. The neutralizing anti-CXCR4 antibody AMD3100 abolished this. In cocultured HR-RTECs the proportions of PCNA+ cells and Bcl-2 expression were enhanced; however, the proportion of annexin V+ cells and expression of cleaved caspase-3 were reduced. The in vivo study showed increased homing of CXCR4-BMSCs in kidneys, which was associated with improved renal function, reduced acute tubular necrosis scoring, accelerated mitogenic response of tubular cells, and reduced tubular cell death. The enhanced homing and paracrine actions of BMSCs with CXCR4 overexpression suggest beneficial effects of such cells in BMSC-based therapy for AKI.

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Lukovic, Dominika, Katrin Zlabinger, Alfred Gugerell, Andreas Spannbauer, Noemi Pavo, Ljubica Mandic, Denise T. Weidenauer et al. « Inhibition of CD34+ cell migration by matrix metalloproteinase-2 during acute myocardial ischemia, counteracted by ischemic preconditioning ». F1000Research 5 (22 novembre 2016) : 2739. http://dx.doi.org/10.12688/f1000research.9957.1.

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Background. Mobilization of bone marrow-origin CD34+ cells was investigated 3 days (3d) after acute myocardial infarction (AMI) with/without ischemic preconditioning (IP) in relation to stromal-derived factor-1 (SDF-1α)/ chemokine receptor type 4 (CXCR4) axis, to search for possible mechanisms behind insufficient cardiac repair in the first days post-AMI. Methods. Closed-chest reperfused AMI was performed by percutaneous balloon occlusion of the mid-left anterior descending (LAD) coronary artery for 90min, followed by reperfusion in pigs. Animals were randomized to receive either IP initiated by 3x5min cycles of re-occlusion/re-flow prior to AMI (n=6) or control AMI (n=12). Blood samples were collected at baseline, 3d post-AMI, and at 1-month follow-up to analyse chemokines and mobilized CD34+ cells. To investigate the effect of acute hypoxia, SDF-1α and matrix metalloproteinase (MMP)-2 in vitro were assessed, and a migration assay of CD34+ cells toward cardiomyocytes was performed. Results. Reperfused AMI induced significant mobilisation of CD34+ cells (baseline: 260±75 vs. 3d: 668±180; P<0.001) and secretion of MMP-2 (baseline: 291.83±53.40 vs. 3d: 369.64±72.89; P=0.011) into plasma, without affecting the SDF-1α concentration. IP led to the inhibition of MMP-2 (IP: 165.67±47.99 vs. AMI: 369.64±72.89; P=0.004) 3d post-AMI, accompanied by increased release of SDF-1α (baseline: 23.80±12.36 vs. 3d: 45.29±11.31; P=0.05) and CXCR4 (baseline: 0.59±0.16 vs. 3d: 2.06±1.42; P=0.034), with a parallel higher level of mobilisation of CD34+ cells (IP: 881±126 vs. AMI: 668±180; P=0.026), compared to non-conditioned AMI. In vitro, CD34+ cell migration toward cardiomyocytes was enhanced by SDF-1α, which was completely abolished by 90min hypoxia and co-incubation with MMP-2. Conclusions. Non-conditioned AMI induces MMP-2 release, hampering the ischemia-induced increase in SDF-1α and CXCR4 by cleaving the SDF-1α/CXCR4 axis, with diminished mobilization of the angiogenic CD34+ cells. IP enforces CD34+ cell mobilization via inhibition of MMP-2.

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Lukovic, Dominika, Katrin Zlabinger, Alfred Gugerell, Andreas Spannbauer, Noemi Pavo, Ljubica Mandic, Denise T. Weidenauer et al. « Inhibition of CD34+ cell migration by matrix metalloproteinase-2 during acute myocardial ischemia, counteracted by ischemic preconditioning ». F1000Research 5 (20 décembre 2016) : 2739. http://dx.doi.org/10.12688/f1000research.9957.2.

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Background. Mobilization of bone marrow-origin CD34+ cells was investigated 3 days (3d) after acute myocardial infarction (AMI) with/without ischemic preconditioning (IP) in relation to stromal-derived factor-1 (SDF-1α)/ chemokine receptor type 4 (CXCR4) axis, to search for possible mechanisms behind insufficient cardiac repair in the first days post-AMI. Methods. Closed-chest reperfused AMI was performed by percutaneous balloon occlusion of the mid-left anterior descending (LAD) coronary artery for 90min, followed by reperfusion in pigs. Animals were randomized to receive either IP initiated by 3x5min cycles of re-occlusion/re-flow prior to AMI (n=6) or control AMI (n=12). Blood samples were collected at baseline, 3d post-AMI, and at 1-month follow-up to analyse chemokines and mobilized CD34+ cells. To investigate the effect of acute hypoxia, SDF-1α and matrix metalloproteinase (MMP)-2 in vitro were assessed, and a migration assay of CD34+ cells toward cardiomyocytes was performed. Results. Reperfused AMI induced significant mobilisation of CD34+ cells (baseline: 260±75 vs. 3d: 668±180; P<0.001) and secretion of MMP-2 (baseline: 291.83±53.40 vs. 3d: 369.64±72.89; P=0.011) into plasma, without affecting the SDF-1α concentration. IP led to the inhibition of MMP-2 (IP: 165.67±47.99 vs. AMI: 369.64±72.89; P=0.004) 3d post-AMI, accompanied by increased release of SDF-1α (baseline: 23.80±12.36 vs. 3d: 45.29±11.31; P=0.05) and CXCR4 (baseline: 0.59±0.16 vs. 3d: 2.06±1.42; P=0.034), with a parallel higher level of mobilisation of CD34+ cells (IP: 881±126 vs. AMI: 668±180; P=0.026), compared to non-conditioned AMI. In vitro, CD34+ cell migration toward cardiomyocytes was enhanced by SDF-1α, which was completely abolished by 90min hypoxia and co-incubation with MMP-2. Conclusions. Non-conditioned AMI induces MMP-2 release, hampering the ischemia-induced increase in SDF-1α and CXCR4 by cleaving the SDF-1α/CXCR4 axis, with diminished mobilization of the angiogenic CD34+ cells. IP might influence CD34+ cell mobilization via inhibition of MMP-2.

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Lukovic, Dominika, Katrin Zlabinger, Alfred Gugerell, Andreas Spannbauer, Noemi Pavo, Ljubica Mandic, Denise T. Weidenauer et al. « Inhibition of CD34+ cell migration by matrix metalloproteinase-2 during acute myocardial ischemia, counteracted by ischemic preconditioning ». F1000Research 5 (6 février 2017) : 2739. http://dx.doi.org/10.12688/f1000research.9957.3.

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Background. Mobilization of bone marrow-origin CD34+ cells was investigated 3 days (3d) after acute myocardial infarction (AMI) with/without ischemic preconditioning (IP) in relation to stromal-derived factor-1 (SDF-1α)/ chemokine receptor type 4 (CXCR4) axis, to search for possible mechanisms behind insufficient cardiac repair in the first days post-AMI. Methods. Closed-chest reperfused AMI was performed by percutaneous balloon occlusion of the mid-left anterior descending (LAD) coronary artery for 90min, followed by reperfusion in pigs. Animals were randomized to receive either IP initiated by 3x5min cycles of re-occlusion/re-flow prior to AMI (n=6) or control AMI (n=12). Blood samples were collected at baseline, 3d post-AMI, and at 1-month follow-up to analyse chemokines and mobilized CD34+ cells. To investigate the effect of acute hypoxia, SDF-1α and matrix metalloproteinase (MMP)-2 in vitro were assessed, and a migration assay of CD34+ cells toward cardiomyocytes was performed. Results. Reperfused AMI induced significant mobilisation of CD34+ cells (baseline: 260±75 vs. 3d: 668±180; P<0.001) and secretion of MMP-2 (baseline: 291.83±53.40 vs. 3d: 369.64±72.89; P=0.011) into plasma, without affecting the SDF-1α concentration. IP led to the inhibition of MMP-2 (IP: 165.67±47.99 vs. AMI: 369.64±72.89; P=0.004) 3d post-AMI, accompanied by increased release of SDF-1α (baseline: 23.80±12.36 vs. 3d: 45.29±11.31; P=0.05) and CXCR4 (baseline: 0.59±0.16 vs. 3d: 2.06±1.42; P=0.034), with a parallel higher level of mobilisation of CD34+ cells (IP: 881±126 vs. AMI: 668±180; P=0.026), compared to non-conditioned AMI. In vitro, CD34+ cell migration toward cardiomyocytes was enhanced by SDF-1α, which was completely abolished by 90min hypoxia and co-incubation with MMP-2. Conclusions. Non-conditioned AMI induces MMP-2 release, hampering the ischemia-induced increase in SDF-1α and CXCR4 by cleaving the SDF-1α/CXCR4 axis, with diminished mobilization of the angiogenic CD34+ cells. IP might influence CD34+ cell mobilization via inhibition of MMP-2.

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Waller, Ned, Arshed Quyyumi, Douglas Vaughan, Thomas Moss, Wai S. Chan, Robert Preti et Andrew L. Pecora. « CD34+CXCR4+ Cell Therapy (AMR-001) for Myocardial Infarction : Preliminary Processing and Product Results of a Phase I Dose Escalation Study. » Blood 110, n^o 11 (16 novembre 2007) : 773. http://dx.doi.org/10.1182/blood.v110.11.773.773.

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Abstract Background: Approximately 20% of patients suffering a ST segment elevated acute myocardial infarction (AMI) have progressive peri-infarct zone myocardial cell death causing ventricular remodeling and poor cardiac outcomes in spite of large vessel revascularization and medical management. Neo-angiogenesis occurs when VEGF levels peak and endothelial precursors are mobilized and recruited to the infarct site. Stromal cell derived factor-1 (SDF-1), the ligand for the CXCR4 receptor, is expressed by CD34+ cells and plays a role in cell homing to areas of ischemic damage. CD34+ CXCR4+ cells home to areas of ischemia, rich in SDF-1, including infarcted myocardium and are capable of inducing neo-angiogenesis. Natural neoangiogenesis is present but insufficient following AMI, suggesting that direct administration of CD34+ CXCR4+ progenitors could mitigate peri-infarct zone myocardial cell death and improve ventricular function. Methods: In this phase I study, patients with an ST segment (AMI) are enrolled in cohorts of 5 to receive one of four doses (5, 10, 15, 20 x 106 of bone marrow derived CD34+ cells. Cells are harvested using a mini-bone marrow harvest (MMH) technique, acquired by Isolex selection and administered by infusion via the infarct related artery 5 to 10 day following successful coronary artery stenting post AMI. The first 10 subjects accrued as subjects on this phase 1 study included 9 males and 1 female, with a median age of 52 years (range 36–70). Results: The first ten patients (of 20 planned) underwent a MMH under conscious sedation without incident. Adequate numbers of viable, enriched CD34+ cells were obtained following Isolex selection for treatment of subjects enrolled at the first two dose cohorts (5 x 106 and 10 x 106 CD34+ cells). The mean fraction of cells expressing CD34 in the marrow product was 0.75%, with a mean recovery of 40% following Isolex selection (Table). Conclusions: Our study demonstrates the feasibility of collecting up to 409 ml of bone marrow using a MMH technique in the immediate post AMI setting, with yields up to 86 x 106 CD34+ cells. All patient cells expressed CXCR4 and had in vitro migratory capacity. However the lower than expected percentage of TNC expressing CD34 (compared with 9 healthy age matched individuals (1.49% vs. 0.75%) and a low % recovery following Isolex selection may limit successful upper (>10 x 106) cohort treatments. VEGf-2 expression on enriched CD34+ cells was variable. Processing and Product Results (N=10) mean (median) range *N=7 (technical loss of 3 samples);** N=9 (technical loss of 1 sample) MMH marrow volume (ml) 395 (396) 377 – 409 Harvest TNC content (x 109) 6.65 ( 6.73) 3.85 – 8.59 Harvest CD34+ content (x 106) 45.3 (50.2) 16.9 – 86.7 Harvest CD34+ % of TNC 0.75% (0.72%) 0.54% – 1.06% Selected CD34+ content (x 106) 17.8 (16.5) 8.4 – 28.9 Selected % CD34+ recovery 40.3% (41.9%) 30.2 – 49.7 Selected %CD34+ viability 97.1% (98.0 %) 96% – 99% Selected % CD34+ purity 82.5% (84.%) 70% – 91% Total processing time (hours) 14.2 (14.0) 11 – 17 SDF-1 induced migration (% of CD34+ cells) 20.2% (17.0%) 9.5% – 35.4% CXCR-4 expression(% of CD34+ cells)* 58.7% (52.0%) 44% – 78% VEGF-2 expression (% of CD34+ cells)** 0.82% (0.86%) 0% – 2.39%

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Zuk, A., M. Gershenovich, Y. Ivanova, R. T. MacFarland, S. P. Fricker et S. Ledbetter. « CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury ». American Journal of Physiology-Renal Physiology 307, n^o 7 (1 octobre 2014) : F783—F797. http://dx.doi.org/10.1152/ajprenal.00685.2013.

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We examined whether antagonism of the CXCR4 receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR4 is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR4 antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR4 inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR4 antagonism with plerixafor may be a potential option to prevent AKI.

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Toosi, Shirin Hamedakbari, Javad Behravan et Asieh Heirani-Tabasi. « Therapeutic Potential of CXCR4/SDF-1 Axis in Acute Myocardial Infarction ». Journal of Genes and Cells 3 (2 mars 2017) : 13. http://dx.doi.org/10.15562/gnc.52.

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Acute Myocardial Infarction (AMI) is one of the mortal diseases which relate to heart and has many impacts on patients’ life. Stem cell therapy, including mesenchymal stem cells (MSCs), has emerged a promise treatment for patients with this disease. However, the inefficient migration and homing of MSCs have limited their therapeutic applications. It has been demonstrated that CXCR4/SDF-1 axis has a crucial role in cell migration and stem cell homing. So, many studies have conducted and currently are operating by novel methods to improve homing of MSCs by up-regulating the expression of CXCR4/SDF-1 axis to discover a proper cell therapy for AMI. CXCR4/SDF-1 axis triggers a variety of biological responses, such as directing cell migration, organogenesis, hematopoiesis, vascularization, and immune responses. Therefore, this axis might be a good candidate for manipulation with therapeutic purposes.

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Huang, Fei, Yunyi Lan, Liyue Qin, Huaihuai Dong, Hailian Shi, Hui Wu, Qinrui Zou, Zhibi Hu et Xiaojun Wu. « Astragaloside IV Promotes Adult Neurogenesis in Hippocampal Dentate Gyrus of Mouse through CXCL1/CXCR2 Signaling ». Molecules 23, n^o 9 (29 août 2018) : 2178. http://dx.doi.org/10.3390/molecules23092178.

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Astragaloside IV (ASI) has been reported to promote neural stem cells proliferation in vitro and CXCR2 expression on neutrophils. The present study was aimed to investigate the influence of ASI on adult neurogenesis in hippocampal dentate gyrus (DGs) of mouse and to discuss the possible underlying mechanisms. Total number of proliferative cells (BrdU+), pre-mature neurons (DCX+), early proliferative cells (BrdU+/DCX+), proliferative radial gila-like cells (BrdU+/GFAP+) and newly generated neurons (BrdU+/NeuN+) after ASI or vehicle administration for two weeks were counted, respectively. The results showed that BrdU+ cells and DCX+ cells were significantly increased in DGs of mice administered with ASI. The numbers of BrdU+/DCX+, BrdU+/GFAP+ cells and BrdU+/NeuN+ cells were also elevated in the ASI group. Correspondingly, ASI increased the protein expression of hippocampal DCX, GFAP and NeuN. Further study disclosed that ASI remarkably up-regulated the mRNA and protein expressions of CXCL1 as well as that of CXCR2 in the hippocampus. The promotive effect of ASI on DCX, GFAP and NeuN protein expression was abolished by SB225002, the inhibitor of CXCR2. Our results indicated that ASI modulated the homeostasis of the CXCL1/CXCR2 signaling pathway, which might be responsible for the increased neurogenesis within the hippocampal DGs of mice.

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Holloman, Bryan L., Mitzi Nagarkatti et Prakash Nagarkatti. « Pulmonary macrophage activation and recruitment in lipopolysaccharide-induced acute lung injury mediates neutrophil infiltration : Role of AhR ligation in intervention ». Journal of Immunology 208, n^o 1_Supplement (1 mai 2022) : 105.36. http://dx.doi.org/10.4049/jimmunol.208.supp.105.36.

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Abstract CCL2-CCR2 signaling plays an essential role in the recruitment of macrophages and neutrophils following tissue injury. During inflammation, CCR2+ macrophage secretion of CCL2 induces an autocrine effect that leads to an intracellular signaling cascade of macrophages that promotes upregulation of CCL2, CXCL2, and CXCL3 expression, which stimulates the chemotaxis of blood circulating CCR2+ monocytes and CXCR2+ neutrophils to the disease site. Interestingly, the aryl hydrocarbon receptor (AhR) ligand has been shown to regulate effector cell recruitment. Therefore, we studied the effects of the AhR ligand, indole-3-carbinol (I3C) on the recruitment of circulating CCR2+ monocytes and CXCR2+ neutrophils during acute lung injury (ALI). To induce ALI in C57BL/6 mice and Ccr2gfp mice (mice deficient in the CCR2 receptor), they were given 5mg/kg of lipopolysaccharide intranasally. Mice were treated with I3C or vehicle following disease induction. Interestingly, I3C downregulated neutrophils expressing CXCR2 (a receptor associated with neutrophil recruitment) and CCR2+ macrophages in lungs of C57BL/6 diseased-mice. Furthermore, to determine if CCR2+ macrophages recruit CXCR2+ neutrophils, we induced ALI in Ccr2gfp mice. Abolishing the expression of CCR2 eliminated the recruitment of CXCR2+ neutrophils to the lungs during ALI. Interestingly, scRNASeq of macrophage/monocyte cells showed that I3C reduced expression of CXCL3. CXCL3 gene translates into the chemokine CXCL3, which binds to CXCR2 and is involved in neutrophil recruitment to the disease site. These findings suggest that CCR2 macrophages are involved in the recruitment of CXCR2+ neutrophils, and the AhR ligand I3C can regulate immune cell trafficking capabilities. Supported by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788, R01AI123947, R01AI160896 and R01AI123947-S2

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Liu, Sheng, Jian Tang, Lei Huang, Qirong Xu, Xiang Ling et Jichun Liu. « Cordyceps Militaris Alleviates Severity of Murine Acute Lung Injury Through miRNAs-Mediated CXCR2 Inhibition ». Cellular Physiology and Biochemistry 36, n^o 5 (2015) : 2003–11. http://dx.doi.org/10.1159/000430168.

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Background/Aims: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are lethal diseases in humans, and the current treatments have limited therapeutic effects. Cordyceps militaris (CM) is a caterpillar-grown traditional medicinal mushroom, and has been used as a natural invigorant for longevity, endurance, and vitality in China. Recently, purified extracts from CM have been shown to have beneficial effects on various diseases including cancer. Nevertheless, a role of CM in ALI has not been examined previously. Methods: Here, we used a bleomycin-induced ALI model to study the effects of CM on the severity of ALI in mice. The levels of CXCR2, a receptor for Interleukin 8 (IL-8) in pulmonary microvascular endothelial cells, were examined in different experimental groups. The levels of microRNA (miR)-1321 and miR-3188 were also examined in lung samples and in CM. Adeno-associated viruses carrying miR-1321 and miR-3188 were injected into bleomycin-treated mice for evaluation their effects on the severity of ALI. Results: CM treatment significantly alleviated the severity of bleomycin-induced ALI in mice. The increases in lung CXCR2 by bleomycin were significantly reduced by CM at protein level, but not at mRNA level. CM contained high levels of 2 miRNAs (miR-1321 and miR-3188) that target 3'-UTR of CXCR2 mRNA to inhibit its expression. Overexpression of miR-1321 and miR-3188 in mouse lung through AAV-mediated gene therapy mimicked the effects of CM. Conclusion: CM may alleviate severity of murine ALI through miRNAs-mediated CXCR2 inhibition.

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Zarbock, Alexander, Jeffrey Bishop, Helena Müller, Mirco Schmolke, Kirsten Buschmann, Hugo Van Aken et Kai Singbartl. « Chemokine homeostasis vs. chemokine presentation during severe acute lung injury : the other side of the Duffy antigen receptor for chemokines ». American Journal of Physiology-Lung Cellular and Molecular Physiology 298, n^o 3 (mars 2010) : L462—L471. http://dx.doi.org/10.1152/ajplung.00224.2009.

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Acute lung injury (ALI) still poses a major challenge in critical care medicine. Neutrophils, platelets, and chemokines are all considered key components in the development of ALI. The Duffy antigen receptor for chemokines (DARC ) is thought to be involved in scavenging, transendothelial transport, and presentation of neutrophil-specific chemokines. DARC is expressed on endothelial cells and erythrocytes but not on leukocytes. Here, we show that DARC is crucial for chemokine-mediated leukocyte recruitment in vivo. However, we also demonstrate that changes in chemokine and chemokine receptor homeostasis, associated with Darc gene deficiency, exert strong anti-inflammatory effects. Neutrophils from Darc gene-deficient ( Darc−/ −) mice display a more prolonged downregulation of CXCR2 during severe inflammation than neutrophils from wild-type mice. In a CXCR2-dependent model of acid-induced ALI, Darc gene deficiency prevents ALI. Darc−/ −mice demonstrate fully preserved oxygenation, only a small increase in vascular permeability, and a complete lack of pulmonary neutrophil recruitment. Further analysis reveals that only neutrophils but neither endothelial cells nor erythrocytes from Darc−/ −mice confer protection from ALI. The protection appears to be due to abolished pulmonary recruitment of neutrophils from Darc−/ −mice. The generation of neutrophil-platelet aggregates, a key mechanism in both pulmonary neutrophil recruitment and thrombus formation, is also affected by altered CXCR2 homeostasis in Darc−/ −mice. CXCR2 blockade enhances the formation of platelet-neutrophil aggregates and thereby corrects a formerly unknown bleeding defect in Darc−/ −mice. In summary, our study suggests that chemokine/chemokine receptor homeostasis plays a previously unrecognized and crucial role in severe ALI.

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Pecora, Andrew L., Robert A. Preti, Wai Shun Chan, Edmund K. Waller, Arshed Quyyumi, Douglas Vaughan et Thomas Moss. « Bone Marrow Derived CD34+CXCR4+ Cells Maintain Viability, Mobility and Sterility up to 72 Hours and Are Compatible with Balloon Dilatation Catheters Used for Intra Coronary Artery Infusion ; Pre-Clinical Development of a Pharmaceutical Grade Cell Therapy for Acute Myocardial Infarction (AMR-001). » Blood 110, n^o 11 (16 novembre 2007) : 1214. http://dx.doi.org/10.1182/blood.v110.11.1214.1214.

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Abstract Background: Approximately 20% of patients suffering a ST segment elevated acute myocardial infarction (AMI) have progressive peri-infarct zone myocardial cell death causing ventricular remodeling and poor cardiac outcomes in spite of standard medical care. Neo-angiogenesis has been proposed as a natural, albeit insufficient response to mitigate ventricular remodeling resulting from an AMI. Stromal derived growth factor-1 (SDF-1), the ligand for the CXCR4 receptor, is expressed by bone marrow derived CD34+ cells and is produced in increased quantities in the peri-infarct zone. CD34+CXCR4+ cells are the cells naturally mobilized from bone marrow following an AMI to induce neo-angiogenesis. Thus we conducted a series of pre-clinical studies to develop a pharmaceutical grade bone marrow derived cell therapy product with neo-angiogenic potential for direct intra-coronary artery infusion in patients following an AMI. Methods: Bone marrow samples were obtained from healthy volunteer donors using a mini-bone marrow harvest technique (MMH). Bone marrow was stored at 4°C for up to 24 hours then processed using Isolex (Baxter, Ill) selection to acquire CD34+ cells, formulated into a delivery apparatus and stored again at 4°C for up to an additional 48 hours in a shipping container. Following storage the cell therapy product was assessed for cell recovery, viability, sterility, CXCR-4 mobility in an SDF-1 gradient, and CFU growth before and after perfusion through the internal port of an intra-coronary artery balloon dilatation catheter. Results :13 donors (11F and 2M), with a median age of 43 years (mean 43; range 21 – 61 years) yielded a median % CD34+ cells of total nucleated cells of 1.45% (mean 1.38%; range 0.92 – 1.71%) with a higher % in males vs. females (1.67 vs.1.33%) and older (≥ 45years) vs. younger (1.49 vs.1.26%) donors. CD34+ cell viability (median 96%; range 91–98%), % CD34+ mobility in an SDF-1 gradient (11.8; 4.5–34%), CFU growth (20; 14–54) and sterility were all maintained for up to 72 hours from MMH (table). Passage of the CD34+ cells through a balloon catheter did not adversely affect any of these parameters including % mobility (at 72 hours n=3; Pre% 34, 6, 18: Post 34, 18, 23). Multiple passages (n=3) through balloon dilatation catheters did not result in significant CD34+ cell loss (median recovery 99%; range 97–111%) or loss of viability (95%; range 92–98%). Conclusion: Bone marrow derived CD34+ cells selected using the Isolex device and formulated for shipping and administration maintain for up to 72 hours a high viability, mobility in an in vitro SDF-1 gradient, CFU potential and remain sterile despite multiple passages through a balloon dilatation catheter without significant cell loss. This formulation (AMR-001) provides a pharmaceutical grade cell therapy for clinical evaluation in AMI. Median (n>3) Hours from MMH 36 hours 60 hours 72 hours Selected CD34+ cell viability % (range) 96 (95–98) 96 (91–97) 97 (91–97) Selected CD34+ mobility % 19 (11–20) 6.2 (4.5–8.8) 18 (5.7–34) CD34+ CFU (colonies) 21 (13–54) 15 (14–28) 27 (14–37)

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Wojakowski, Wojciech, Michal Tendera, Magdalena Kucia, Ewa K. Zuba-Surma, Edyta Paczkowska, Joanna Ciosek, Maciek Halasa et al. « Clinical Evidence That Oct-4+ ssea-4+ Very Small Embryonic Like Stem Cells (VSEL) Are Mobilized into Peripheral Blood in Patients with Acute Myocardial Infarction (AMI) : A Novel Prognostic Indicator ». Blood 112, n^o 11 (16 novembre 2008) : 2894. http://dx.doi.org/10.1182/blood.v112.11.2894.2894.

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Abstract We demonstrated that murine bone marrow (BM) contains a mobile population of CXCR4+SSEA-1+Sca-1+lin CD45− very small embryonic like (VSEL) stem cells (Leukemia2006:20; 857) that are mobilized into peripheral blood (PB) in SDF-1 dependent manner in murine model of acute myocardiac infarct (AMI) (J Moll Cell Cardiol2008,44, 865–873). Since a similar population of CXCR4+CD133+CD34+SSEA-4+Oct-4+lin−CD45− cells resides also in human BM (Leukemia2007:21;297), we asked whether in humans, similarly as in mice, the AMI-related stress may trigger mobilization of these cells from BM into PB. To address this question, we evaluated the mobilization of VSEL in patients with AMI, measured expression of pluripotential stem cell (PSC), cardiac and endothelial markers in peripheral blood mononuclear cells and purified by FACS VSEL, and finally assessed the factors influencing mobilization of VSEL and correlation of cell number with left ventricular ejection fraction (LVEF). Totally, 31pts with AMI and 30 healthy subjects were enrolled. Peripheral blood was sampled on admission, after 24 hours and 5 days VSEL were enumerated by FACS and sorted by Facs-Aria. Presence of PSC markers (Oct-4, SSEA-4) and chemokine receptor CXCR4 in circulating VSEL was confirmed at the protein level immunofluorescent staining and ImageStream system (ISS) analysis. Plasma levels of SDF-1, HGF, VEGF, G-CSF were measured by ELISA. We noticed that in healthy subjects median number of circulating VSEL is very low [0.8 (0–1.3] cells/μL. In AMI VSEL were mobilized early [2.7 (0.2–3.9) cells/μL; p<0.001), and remained elevated after 24 hrs and 5 days [4.7 (0.2–7.4); p<0.001 and 2.6 (0.3–3.6) cells/μL; p<0.03, respectively]. Circulating VSELs were enriched in mRNA of PSC markers (Oct-4: 206±3-fold; Nanog: 282,1±4-fold), cardiac lineage (GATA-4, Nkx2.5/Csx, MEF2C) and endothelial (VE-cadherin) markers. Highest relative expression level was detected after 24h after acute MI. VSEL size - cell diameter was approx. 7–8 μm. The mobilization of VSEL after 12 and 24 hrs was significantly higher in patients younger than 50y [4.9 (0–6.4) vs. 2.7 (0.2–5.1) cells/μL; P<0.05]. In patients with diabetes the number of mobilized VSEL after 12 and 24 hrs was significantly lower than in those without diabetes [1.9 (0–2.3) vs. 4.8 (0.2–6.2) cells/μL; P<0.05]. Mobilization of VSEL was impaired in patients with LVEF <40% in comparison to LVEF >40% [3.3 (0–4.9) vs. 4.7 (0.4–6.4) cells/μL; P<0.05]. Of note VSEL showed significant negative correlations with cardiac necrosis markers (maximum activity of CK-MB and troponin I) after 12 and 24 hrs, but not 5 days (R=−0.41, R=−0.45). Thus, for the first time in humans we provide evidence that AMI induces mobilization of VSEL expressing pluripotent markers as well SDF-1 binding receptor CXCR4. Mobilization of VSEL is impaired in older patients with diabetes and reduced LVEF. Number of mobilized VSEL is inversely correlated with myocardial necrosis markers and positively with SDF-1 levels.

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Lange, A., W. Witkiewicz, D. Dlubek, L. Maslowski, D. Drabczak-Skrzypek, E. Jaskula, B. Szymczak, D. Duda et J. Lange. « A Bone Marrow Population Containing Both Hematopoietic and Mesenchymal Stem Cells Constitutively Expressing Genes Pairs For : SDF1-CXCR4, CX3CL-CXCR1 and for VEGF Improves Vascularization When Implanted to Ischemic Legs. » Blood 104, n^o 11 (16 novembre 2004) : 4178. http://dx.doi.org/10.1182/blood.v104.11.4178.4178.

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Abstract The BM contains progenitor cells that give rise to hematopoietic tissue and also more primitive mesenchymal stem cells (MSC) which may differentiate into other tissues including endothelial cells. This potential of BM cells has already been employed in clinical studies suggesting that implantation of autologous BM cells may induce angiogenesis in ischemic tissues. In the present study 10 male pts with critical leg ischemia (41–64 yrs) suffering from pain at rest and/or foot ischemic ulceration (9/10 pts) with ABI (ankle/brachial index) <0.5 in 8/10 pts in whom surgical treatments were exhausted were enrolled in this study. 0.5L of BM obtained from the iliac posterior crest were processed in a Cobe Spectra 6.0 separator to remove RBC and to reduce the number of granulocytes. Fresh BM populations and those after processing were evaluated for phenotype characteristics and for the presence of transcripts for VEGF and for SDF1-CXCR4, CX3CL-CXCR1 gene pair expression. Usually 40 ml of cell suspensions were injected in 0.5 ml portions to ischemic muscles and the fate of the pts was evaluated in an out-pts observation setting for 5–7 mths. The number of WBC implanted was (mean±SEM) 30.2x108±4.5 which contained the following percentages of subpopulations CD34+ 1.58±0.25, CD45−CD34− 10.8±0.96, CD45−CD34−CD90+ 0.1±0.02, CD45−CD34−CD105+ 2.8±0.4, CD45−CD34−CD73+ 0.07±0.01 and 24 CFU-F/106 WBC. The positive effect of implantation was seen 2 days after the procedure with substantial pain reduction from 6.17±0.35 to 4.63±1.03 (p=0.04) 10 days and to 3.66±1.35 3 mths after implantation (p=0.034). ABI improved from 0.47±0.07 before to 0.66±0.06 (p=0.02) 10 days and to 0.66±0.07 (p=0.02) 3 mths after. This improvement was followed by ulceration healing in 5/9 pts (area of ulceration prior to implantation was 502.3±269.2 mm2 and 2 mths after was 32.3±23.6 mm2) in 2 pts ulceration healed completely. In 10 cases arteriography performed 3 mths after implantation documented new arteriole formation in 6 pts. The positive effect may not be long lasting in all pts as in 3/10 pts the pain at rest recurred and in 2 pts ulceration progressed 2 mths after implantation. The positive effect of the treatment could not be attributed to any of the described cell populations separately as evaluated by correlation analysis. In this study we identified cells with MSC characteristics in the BM population that were further enriched in MNC and implanted to ischemic muscles. In fresh BM cell populations and those after cell processing, the transcripts for VEGF and SDF1-CXCR4 and CXCL3-CXCR1 pairs were found. Implantation of these cells resulted in early, intermediate and late effects with pain relief, ischemic ulceration healing and finally arteriole length density, respectively. The pace of improvement suggested that the processed BM population while injected to ischemic muscles may act via cyto-/chemokine release with an analgetic effect and local immunity improvement. Furthermore, ulceration healing seen 10 days after implantation followed by neovascularization is likely due to auto/paracrine effects within a population of MSC that express genes facilitating the homing of vascular progenitors and play a role in new vessels formation. Supp by the grant PBZ-KBN-083/P05/2002 from the Polish State Committee Sci. Res.

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Ahuja, Nilesh, Ana Andres-Hernando, Christopher Altmann, Rhea Bhargava, Jasna Bacalja, Ryan G. Webb, Zhibin He, Charles L. Edelstein et Sarah Faubel. « Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice ». American Journal of Physiology-Renal Physiology 303, n^o 6 (15 septembre 2012) : F864—F872. http://dx.doi.org/10.1152/ajprenal.00025.2012.

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Serum IL-6 is increased in patients with acute kidney injury (AKI) and is associated with prolonged mechanical ventilation and increased mortality. Inhibition of IL-6 in mice with AKI reduces lung injury associated with a reduction in the chemokine CXCL1 and lung neutrophils. Whether circulating IL-6 or locally produced lung IL-6 mediates lung injury after AKI is unknown. We hypothesized that circulating IL-6 mediates lung injury after AKI by increasing lung endothelial CXCL1 production and subsequent neutrophil infiltration. To test the role of circulating IL-6 in AKI-mediated lung injury, recombinant murine IL-6 was administered to IL-6-deficient mice. To test the role of CXCL1 in AKI-mediated lung injury, CXCL1 was inhibited by use of CXCR2-deficient mice and anti-CXCL1 antibodies in mice with ischemic AKI or bilateral nephrectomy. Injection of recombinant IL-6 to IL-6-deficient mice with AKI increased lung CXCL1 and lung neutrophils. Lung endothelial CXCL1 was increased after AKI. CXCR2-deficient and CXCL1 antibody-treated mice with ischemic AKI or bilateral nephrectomy had reduced lung neutrophil content. In summary, we demonstrate for the first time that circulating IL-6 is a mediator of lung inflammation and injury after AKI. Since serum IL-6 is increased in patients with either AKI or acute lung injury and predicts prolonged mechanical ventilation and increased mortality in both conditions, our data suggest that serum IL-6 is not simply a biomarker of poor outcomes but a pathogenic mediator of lung injury.

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Su, Vincent Yi-Fong, Wei-Chih Chen, Wen-Kuang Yu, Huai-Hsuan Wu, Hao Chen et Kuang-Yao Yang. « Nintedanib Regulates GRK2 and CXCR2 to Reduce Neutrophil Recruitment in Endotoxin-Induced Lung Injury ». International Journal of Molecular Sciences 22, n^o 18 (13 septembre 2021) : 9898. http://dx.doi.org/10.3390/ijms22189898.

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The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsis-induced acute lung injury (ALI) remains unclear. Lipopolysaccharide (LPS), also known as endotoxin, has been used to induce ALI. The goal of this study was to assess the effect of nintedanib in attenuating the histopathological changes of LPS-induced ALI. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h and 10 min before intratracheal endotoxin instillation. Lung histopathological characteristics, adhesion molecule expression, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed after 24 h. We found that nintedanib significantly reduced histopathological changes and neutrophil recruitment in LPS-induced ALI. The number of neutrophils in bronchoalveolar lavage fluid (BALF) was reduced in nintedanib-treated relative to untreated mice with ALI. Nintedanib mediated the downregulation of the chemotactic response to LPS by reducing the expression of adhesion molecules and the phosphorylated p38:total p38 mitogen-activated protein kinase (MAPK) ratio in the lungs of mice with ALI. Nintedanib also reduced the expression of lymphocyte antigen 6 complex locus G6D (Ly6G) and very late antigen 4 (VLA-4) in BALF neutrophils and mediated the downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in mice with LPS-induced ALI. Nintedanib improved the histopathological changes of LPS-induced ALI by reducing neutrophil chemotaxis. These effects were mediated by the inhibition of adhesion molecules via the activation of GRK2 and the inhibition of p38 MAPK and CXCR2.

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Latif, Ahmed Abdel, Anush K. Karapetyan, Yuri Klyachkin, Manjula Sunkara, Susan Smyth, Mariusz Z. Ratajczak et Andrew J. Morris. « Novel Role for Bioactive Lipids in Mobilization of Bone Marrow Stem Cells During Myocardial Ischemia : Sphingosine-1 Phosphate (S1P) As Potential Therapeutic Target ». Blood 120, n^o 21 (16 novembre 2012) : 1911. http://dx.doi.org/10.1182/blood.v120.21.1911.1911.

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Abstract Abstract 1911 Background: Bone marrow (BM) contains a variety of stem cells, including mobile pool of hematopoietic stem cells and non-hematopoietic stem cells and acute myocardial infarction (AMI) triggers mobilization of BM-derived stem cells (BMSCs) through poorly understood processes. Recently we have postulated a major role for bioactive lipids such as sphingosine-1 phosphate (S1P) in G-CSF- and AMD3100-induced mobilization of hematopoietic stem cells (HSCs) into peripheral blood (PB) (Leukemia 2010;24:976–85). Hypothesis: We hypothesized that S1P could also play a role in mobilization of BMSCs in patients during tissue and organ injury as seen for example in patients with AMI. Methods: Peripheral blood (PB) samples from matched controls and patients presenting with ST-elevation myocardial infarction (STEMI) were examined i) by employing FACS for a number of circulating in PB lineage negative (Lin-)/CD45-/CD34+ and CD133+ and CXCR4+ BMSCs, ii) PB level of S1P by employing mass spectrometry, iii) SDF-1 level by ELISA and finally iv) BMSCs were tested in Transwell migration assays for their chemotactic responsiveness to S1P gradient in plasma from STEMI patients. Results: Plasma S1P levels were highest within 6 hours of AMI presentation 0.31 ± 0.02 μM and declined to 0.14 ± 0.02 μM in controls (P < 0.05 for 6 hours vs. controls). The elevation of plasma S1P corresponded with complement cascade (CC) activation and higher levels of C5b-C9 membrane attack complex (MAC) complex in the plasma. The largest reservoir of S1P in whole blood was red blood cells (RBCs) and incubation of RBCs with activated complement initiated the release of S1P. Elevated plasma S1P levels was paralleled by early significant increase in circulating lineage negative (Lin-)/CD45-/CD34+, CD133+ and CXCR4+ BMSCs (P < 0.01 vs. controls). Plasma obtained from STEMI patients in the early phases following acute injury stimulated the migration of human BM-derived Lin-/CXCR4+ and Lin-/CD34+ BMSCs in chemotaxis assays (7–8-fold increase vs. vehicle, P < 0.05), this effect was blunted by charcoal stripping of the plasma (CSP) and was further inhibited by the specific S1P receptor type 1 (S1P1) antagonists W146 (10 μM) and VPC20139 (10 μM). At the same time to our surprise we did not observed significant chemotactic relevant changes in SDF-1 level in PB plasma. Conclusion: This is the first human study to suggest that elevated S1P level in PB early in the course of AMI mobilizes BMSCs. Furthermore, we demonstrate for the first time that the release of hematopoietic and non-hematopoietic BMSCs into PB correlates in AMI patients with activation of CC and generation of MAC, that may release S1P from erythrocytes and platelets. We postulate that based on these results future studies examining the therapeutic manipulation of S1P and its receptors for myocardial regeneration are warranted. Disclosures: No relevant conflicts of interest to declare.

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Dong, Yuan, Weining Kong et Wei An. « Downregulation of Augmenter of Liver Regeneration Impairs the Therapeutic Efficacy of Liver Epithelial Progenitor Cells Against Acute Liver Injury by Enhancing Mitochondrial Fission ». Stem Cells 39, n^o 11 (2 août 2021) : 1546–62. http://dx.doi.org/10.1002/stem.3439.

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Abstract Cell-based therapeutic approaches have been proven to be effective strategies for the treatment of acute liver injury (ALI). However, widespread application of these procedures is limited by several key issues, including rapid loss of stemness in vitro, aberrant differentiation into undesirable cell types, and low engraftment in vivo. In this study, liver epithelial progenitor cells (LEPCs) were characterized and transfected with augmenter of liver regeneration (ALR). The results revealed that in ALI mice with CCl4, the transplantation of ALR-bearing LEPCs into the liver markedly protected mice against ALI by decreasing the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), thus relieving hepatic tissue injury and attenuating inflammatory infiltration. Mechanistically, the knockdown of ALR in LEPCs activated the phosphorylation of dynamin-related protein 1 (Drp1) at the S616 site and thereby enhanced mitochondrial fission. In contrast, the transfection of ALR into LEPCs significantly inhibited Drp1 phosphorylation, thereby favoring the maintenance of mitochondrial integrity and the preservation of adenosine triphosphate contents in LEPCs. Consequently, the ALR-bearing LEPCs transplanted into ALI mice exhibited substantially greater homing ability to the injured liver via the SDF-1/CXCR4 axis than that of LEPCs-lacking ALR. In conclusion, we demonstrated that the transplantation of ALR-transfected LEPCs protected mice against CCl4-induced ALI, thus offering immense curative potential in the clinic.

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Sung, Pei-Hsun, Tsung-Cheng Yin, Christopher Glenn Wallace, Kuan-Hung Chen, Pei-Lin Shao, Fan-Yen Lee, Cheuk-Kwan Sun et al. « Extracorporeal Shock Wave-Supported Adipose-Derived Fresh Stromal Vascular Fraction Preserved Left Ventricular (LV) Function and Inhibited LV Remodeling in Acute Myocardial Infarction in Rat ». Oxidative Medicine and Cellular Longevity 2018 (17 octobre 2018) : 1–22. http://dx.doi.org/10.1155/2018/7518920.

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This study tested the hypothesis that extracorporeal shock wave- (ECSW-) assisted adipose-derived stromal vascular fraction (SVF) therapy could preserve left ventricular ejection fraction (LVEF) and inhibit LV remodeling in a rat after acute myocardial infarction (AMI). Adult male SD rats were categorized into group 1 (sham control), group 2 (AMI induced by left coronary artery ligation), group 3 [AMI + ECSW (280 impulses at 0.1 mJ/mm2, applied to the chest wall at 3 h, days 3 and 7 after AMI), group 4 [AMI + SVF (1.2 × 106) implanted into the infarct area at 3 h after AMI], and group 5 (AMI + ECSW-SVF). In vitro, SVF protected H9C2 cells against menadione-induced mitochondrial damage and increased fluorescent intensity of mitochondria in nuclei (p<0.01). By day 42 after AMI, LVEF was highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, and similar between the latter two groups (all p<0.0001). LV remodeling and infarcted, fibrotic, and collagen deposition areas as well as apoptotic nuclei exhibited an opposite pattern to LVEF among the groups (all p<0.0001). Protein expressions of CD31/vWF/eNOS/PGC-1α/α-MHC/mitochondrial cytochrome C exhibited an identical pattern, whilst protein expressions of MMP-9/TNF-α/IL-1β/NF-κB/caspase-3/PARP/Samd3/TGF-β/NOX-1/NOX-2/oxidized protein/β-MHC/BNP exhibited an opposite pattern to LVEF among five groups (all p<0.0001). Cellular expressions of CXCR4/SDF-1α/Sca-1/c-Kit significantly and progressively increased from groups 1 to 5 (all p<0.0001). Cellular expression of γ-H2AX/CD68 displayed an opposite pattern to LVEF among the five groups (all p<0.0001). In conclusion, ECSW-SVF therapy effectively preserved LVEF and inhibited LV remodeling in rat AMI.

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Sun, Jiayin, Jun Xie, Lina Kang, Albert Ferro, Li Dong et Biao Xu. « Amlodipine Ameliorates Ischemia-Induced Neovascularization in Diabetic Rats through Endothelial Progenitor Cell Mobilization ». BioMed Research International 2016 (2016) : 1–13. http://dx.doi.org/10.1155/2016/3182764.

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Objectives. We investigated whether amlodipine could improve angiogenic responses in a diabetic rat model of acute myocardial infarction (AMI) through improving bone marrow endothelial progenitor cell (EPC) mobilization, in the same way as angiotensin converting enzyme inhibitors.Methods. After induction of AMI by coronary artery ligation, diabetic rats were randomly assigned to receive perindopril (2 mgkg−1 day−1), amlodipine (2.5 mgkg−1 day−1), or vehicle by gavage (n=20per group). Circulating EPC counts before ligation and on days 1, 3, 5, 7, 14, and 28 after AMI were measured in each group. Microvessel density, cardiac function, and cardiac remodeling were assessed 4 weeks after treatment. The signaling pathway related to EPC mobilization was also measured.Results. Circulating EPC count in amlodipine- and perindopril-treated rats peaked at day 7, to an obvious higher level than the control group peak which was reached earlier (at day 5). Rats treated with amlodipine showed improved postischemia neovascularization and cardiac function, together with reduced cardiac remodeling, decreased interstitial fibrosis, and cardiomyocyte apoptosis. Amlodipine treatment also increased cardiac SDF-1/CXCR4 expression and gave rise to activation of VEGF/Akt/eNOS signaling in bone marrow.Conclusions. Amlodipine promotes neovascularization by improving EPC mobilization from bone marrow in diabetic rats after AMI, and activation of VEGF/Akt/eNOS signaling may in part contribute to this.

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Klyachkin, Yuri M., Anush V. Karapetyan, Mariusz Z. Ratajczak et Ahmed Abdel-Latif. « The Role of Bioactive Lipids in Stem Cell Mobilization and Homing : Novel Therapeutics for Myocardial Ischemia ». BioMed Research International 2014 (2014) : 1–12. http://dx.doi.org/10.1155/2014/653543.

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Despite significant advances in medical therapy and interventional strategies, the prognosis of millions of patients with acute myocardial infarction (AMI) and ischemic heart disease (IHD) remains poor. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infarcted myocardium. It is now well established that cardiomyocytes undergo continuous renewal, with contribution from bone marrow (BM)-derived stem/progenitor cells (SPCs). This phenomenon is upregulated during AMI by initiating multiple innate reparatory mechanisms through which BMSPCs are mobilized towards the ischemic myocardium and contribute to myocardial regeneration. While a role for the SDF-1/CXCR4 axis in retention of BMSPCs in bone marrow is undisputed, its exclusive role in their mobilization and homing to a highly proteolytic microenvironment, such as the ischemic/infarcted myocardium, is currently being challenged. Recent evidence suggests a pivotal role for bioactive lipids in the mobilization of BMSPCs at the early stages following AMI and their homing towards ischemic myocardium. This review highlights the recent advances in our understanding of the mechanisms of stem cell mobilization, provides newer evidence implicating bioactive lipids in BMSPC mobilization and differentiation, and discusses their potential as therapeutic agents in the treatment of IHD.

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Tao, Zhengang, Ying Yuan et Qingwu Liao. « Alleviation of Lipopolysaccharides-Induced Acute Lung Injury by MiR-454 ». Cellular Physiology and Biochemistry 38, n^o 1 (2016) : 65–74. http://dx.doi.org/10.1159/000438609.

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Background/Aims: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI.

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Gu, Jun-Yi, Hui-Fen Shi, Xiu-Li Gao, Qing-Qing Ma et Bo Zhang. « Effect of CXCR4 pretreated with ultrasound-exposed microbubbles on accelerating homing of bone marrow mesenchymal stem cells to ischemic myocardium in AMI rats ». Asian Pacific Journal of Tropical Medicine 8, n^o 9 (septembre 2015) : 766–71. http://dx.doi.org/10.1016/j.apjtm.2015.07.027.

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Liu, Xiaohu, Clark Fruhstorfer, Katharina Rothe et Xiaoyan Jiang. « A New AHI-1-DNM2-BCR-ABL Complex Regulates Leukemic Properties of Primitive CML Cells through Mediation of Cellular Endocytosis and ROS-Induced Autophagy ». Blood 126, n^o 23 (3 décembre 2015) : 52. http://dx.doi.org/10.1182/blood.v126.23.52.52.

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Abstract Tyrosine kinase inhibitor (TKI) therapies have been introduced into clinical practice with remarkable effects on chronic phase CML. However, early relapses, acquired drug resistance, and persistence of leukemic stem cells (LSCs) remain problematic. Improved treatment approaches to specifically target key molecular elements active in CML LSCs are needed. One candidate is the adaptor protein AHI-1 (Abelson helper integration site-1), an oncogene that is highly deregulated in LSCs. An AHI-1-mediated protein complex containing BCR-ABL and JAK2 has been shown to modulate transforming activity and TKI-response/resistance of CML LSCs. We have recently identified the large GTPase Dynamin-2 (DNM2) as another AHI-1 interacting protein using the AHI-1 SH3 domain as protein "bait" in immunoprecipitation (IP)/mass spectrometry. DNM2 plays key roles in the regulation of trafficking processes such as endocytosis, and is activated through tyrosine phosphorylation. However, its role in CML pathogenesis is unknown. We have now demonstrated that transcript levels of DNM2 are significantly increased in treatment-naive CD34+ cells from CML patients who were classified retrospectively, after Imatinib (IM) therapy, as IM-responders (n=11) and IM-nonresponders (n=15) in comparison to CD34+ normal bone marrow cells (n=7, p=0.013 and 0.037). In particular, DNM2 is more highly expressed in CML stem-enriched cells (lin-CD34+CD38-) and progenitor cells (lin-CD34+CD38+) than more mature cells (lin+CD34-, 2-fold). Interestingly, BCR-ABL+ human cells with stable knockdown of DNM2 exhibited significantly reduced cell growth and increased apoptosis as compared to control cells. They also showed enhanced sensitivity to single TKIs or MitMAB (DNM2 inhibitor) and these effects were greatly enhanced by combination treatments (2-3 fold). Mechanistically, co-IP and confocal co-localization analysis with mutant forms of AHI-1 and DNM2 (HA-AHI-1, HA-AHI-1 SH3Δ, Myc-DNM2 and Myc-DNM2 PRDΔ) in 293T cells indicated that the PRD domain of DNM2 is mainly responsible for the interaction between the SH3 domain of AHI-1 and DMN2. More importantly, we identified a new protein interaction between DNM2 and BCR-ABL in both BCR-ABL and BCR-ABL/AHI-1 co-transduced hematopoietic cells using co-IP/Western analysis; this interaction is enhanced in BCR-ABL/AHI-1 co-transduced cells. Moreover, DNM2 phosphorylation was decreased upon IM treatment in BCR-ABL-transduced cells, but remained unchanged in control and T315I mutant cells, suggesting that DNM2 is a direct target of BCR-ABL. Interestingly, we further observed that AHI-1 co-localizes with EEA-1 (early endosome marker) and LAMP-1 (late endosome marker) in cells co-transfected with full-length AHI-1 and DNM2, but not in AHI-1 and DNM2 mutant cells. Using transferrin uptake assays, increased transferrin signals were observed in BCR-ABL/AHI-1 co-transduced cells compared to BCR-ABL- and BCR-ABL/AHI-1 SH3Δ-transduced cells, while transferrin signals were much lower in DNM2-knockdown cells than control cells. These results suggest that the AHI-1-DNM2-BCR-ABL complex indeed improves the kinetics and increases efficiency of endocytosis, which may contribute to response/resistance of primitive CML cells to TKIs. This is further supported by observation of increased surface expression levels of CXCR4 in DNM2 knockdown cells, a key endocytotic target and known mediator of TKI response in CML. Moreover, reactive oxygen species (ROS) signals were found to be higher in BCR-ABL/AHI-1 co-transduced cells than BCR-ABL- and BCR-ABL/AHI-1 SH3Δ-transduced cells, while ROS accumulation was significantly decreased in DNM2-knockdown cells compared to control cells. More interestingly, ROS-induced autophagy was further observed in BCR-ABL/AHI-1 co-transduced cells, but reduced in DNM-2-knockdown cells, with protein expression changes in key autophagy proteins, including ULK-1, Beclin-1, LC3 and p62. To the best of our knowledge, this is the first study to implicate a new AHI-1-DNM2-BCR-ABL complex in the deregulation of endocytosis signaling and ROS production/autophagy in CML. This may play a unique and important role in the regulation of cellular properties of primitive CML cells, including their response/resistance to TKI. Disclosures No relevant conflicts of interest to declare.

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Koutsogiannaki, Sophia, et Koichi Yuki. « Elucidating the mechanism of neutrophil-mediated lung injury in sepsis and the role of CD11d/CD18 integrin on this process ». Journal of Immunology 208, n^o 1_Supplement (1 mai 2022) : 105.21. http://dx.doi.org/10.4049/jimmunol.208.supp.105.21.

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Abstract Sepsis is the leading cause of death in intensive care unit (ICU) and the most expensive condition treated in the US, without a specific therapy yet available. Acute lung injury (ALI) is one of the most significant organ injuries in sepsis, resulting from massive migration of neutrophils to the lung, but the exact mechanism is not known. β2 (CD18) integrin family [consisting of αLβ2 (CD11a/CD18), αMβ2 (CD11b/CD18), αXβ2 (CD11c/CD18) and αDβ2 (CD11d/CD18)] and its counter-receptor on the endothelium, ICAM-1 (CD54), are critical for neutrophil migration, but their role in ALI is not yet delineated. Using a murine model of sepsis induced by cecal ligation and puncture (CLP) surgery, we showed decreased neutrophil levels and attenuated injury in the lung of β2−/− and ICAM-1−/− mice at 12h post-CLP, suggesting the importance of β2 integrins in this process. In addition, we observed decreased neutrophil levels and attenuated injury in the lung of αDβ2−/− mice but not in the lung of αLβ2−/− and αMβ2−/− mice, suggesting that αDβ2 has an orchestrating role in sepsis-induced ALI. In support, we found increased αDβ2 expression levels on neutrophils both in the lung and blood of WT mice as sepsis progressed. RNAseq analysis in neutrophils from blood and lung of WT and αDβ2−/− mice showed that αDβ2 mediates neutrophil migration to the lung through pathways associated with antigen presentation, apoptosis and NOD-like receptor signaling. αDβ2−/− neutrophils had also less Cxcr2, Ltb4r1 and Dhrs9 expression, associated with neutrophil migration and the retinoic acid pathway. Taken together, our results suggest a mechanism for ALI in sepsis in which αDβ2 integrin has a major role and could be a novel target for therapeutic intervention. The Anesthesia Research Distinguished Trailblazer Award, Boston Children's Hospital The William F. Milton Fund, Harvard University

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Koutsogiannaki, Sophia, Alvin T. Kho et Koichi Yuki. « Unraveling the role of β2 integrins in neutrophil migration to the lung and subsequent acute lung injury in sepsis ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 220.13. http://dx.doi.org/10.4049/jimmunol.204.supp.220.13.

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Abstract Sepsis is the leading cause of death in intensive care units but not specific therapy is yet available. Acute lung injury (ALI) is a major complication in sepsis, resulting from massive migration of neutrophils to the lung, but the exact mechanism is not known. β2 (CD18) integrin family [consisting of αLβ2 (CD11a/CD18), αMβ2 (CD11b/CD18), αXβ2 (CD11c/CD18) and αDβ2 (CD11d/CD18)] and its counter-receptor on the endothelium, ICAM-1 (CD54), are critical for neutrophil migration, but their role in ALI is not yet delineated. Using a murine model of sepsis induced by cecal ligation and puncture (CLP) surgery, we showed decreased neutrophil levels and attenuated injury in the lung of β2−/− and ICAM-1−/−mice at 12h post-CLP, suggesting the importance of β2 integrins in this process. In addition, we observed decreased neutrophil levels and attenuated injury in the lung of αDβ2−/− mice but not in the lung of αLβ2−/− and αMβ2−/− mice, suggesting that among β2 integrins, αDβ2 has an orchestrating role in neutrophil migration to the lung and subsequent ALI in sepsis. In support, we found increased αDβ2 expression levels on neutrophils in the lung and blood of WT mice as sepsis progressed. RNAseq analysis in neutrophils from blood and lung of WT and αDβ2−/− mice showed that αDβ2 mediates neutrophil migration to the lung through pathways associated with antigen representation, maturation, apoptosis and NOD-like receptor signaling. αDβ2−/− neutrophils had also less Cxcr2, Ltb4r1 and Dhrs9 expression, associated with neutrophil migration and the retinoic acid pathway. Together, our results suggest a mechanism for neutrophil migration to the lung and subsequent ALI in sepsis in which αDβ2 has a major role and could be a novel target for therapeutic intervention.

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Iwakura, Takamasa, Zhibo Zhao, Julian A. Marschner, Satish Kumar Devarapu, Hideo Yasuda et Hans Joachim Anders. « Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration ». Nephrology Dialysis Transplantation 34, n^o 10 (8 janvier 2019) : 1669–80. http://dx.doi.org/10.1093/ndt/gfy397.

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AbstractBackgroundCisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI.MethodsIn in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay.ResultsIn in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG.ConclusionsThe DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.

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Amanda, Stella, Tze King Tan, Jolynn Zu Lin Ong, Madelaine Skolastika Theardy, Regina Wan Ju Wong, Xiao Zi Huang, Muhammad Zulfaqar Ali et al. « Abstract LB018 : Clonal evolution and lineage choice driven by IRF4 in zebrafish T-cell lymphoma model ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : LB018. http://dx.doi.org/10.1158/1538-7445.am2022-lb018.

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Abstract IRF4 is a master regulator of immunity and is also frequently overexpressed in mature lymphoid neoplasms. Here, we demonstrate the stage-specific oncogenicity of IRF4 in vivo, its potential effects on T-cell development and clonal evolution using a zebrafish model. IRF4-transgenic zebrafish develop aggressive tumors with massive infiltration of abnormal lymphocytes that spread to distal organs. Many late-stage tumors are mono- or oligoclonal, and tumor cells can expand in recipient animals after transplantation, demonstrating their malignancy. Mutation of p53 significantly accelerates tumor onset, increases penetrance, and results in tumor heterogeneity. Unexpectedly, single-cell RNA-sequencing reveals that majority of tumor cells are double-negative T-cells, many of which express tcr-γ that became dominant as the tumors progress, whereas double-positive T-cells are largely diminished. Gene expression and enhancer profiling demonstrates that gata3, mycb and several genes that were previously not implicated in cancers including lrrn1, patl1 and psip1 are specifically upregulated in tumors, while genes responsible for T-cell differentiation including cxcr4b, id3 and cd8a are repressed. IRF4-driven tumors are sensitive to treatment with the BRD inhibitor (JQ1). Citation Format: Stella Amanda, Tze King Tan, Jolynn Zu Lin Ong, Madelaine Skolastika Theardy, Regina Wan Ju Wong, Xiao Zi Huang, Muhammad Zulfaqar Ali, Li Yan, Zhiyuan Gong, Hiroshi Inagaki, Ee Yong Foo, Brendan Pang, Soo Yong Tan, Shinsuke Iida, Takaomi Sanda. Clonal evolution and lineage choice driven by IRF4 in zebrafish T-cell lymphoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB018.

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Treon, Steven P., Christian Buske, Sheeba K. Thomas, Jorge J. Castillo, Andrew R. Branagan, Meletios A. Dimopoulos, Maria Gavriatopoulou et al. « Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations ». Blood 138, Supplement 1 (5 novembre 2021) : 1362. http://dx.doi.org/10.1182/blood-2021-144706.

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Abstract Background: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by expansion of clonal IgM-secreting cells (Advani P, et al. Hematol Oncol Stem Cell Ther. 2019;12:179-188). While ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) currently approved by the US FDA and EMA for WM, other BTKi's are currently under investigation. More than 90% of patients with WM have somatic mutations in MYD88, and 30%-40% of these patients have activating mutations in CXCR4WHIM (Xu L, et al. Br J Haematol. 2016;172:735-744; Treon SP, et al. Blood. 2014;123:2791-2796). CXCR4WHIM in WM is associated with high serum IgM level, symptomatic hyperviscosity, earlier time to treatment, and inferior response to approved and investigational BTKi (Schmidt J, et al. Br J Haematol. 2015;169:795-803;Tam C, et al. Blood. 2020; 136:2038-2050). Inhibition of CXCR4 can sensitize CXCR4WHIM-expressing cells to ibrutinib (Cao Y, et al. Leukemia. 2015;29:169-176). Mavorixafor is an oral small-molecule antagonist of CXCR4. In vitro data have shown that mavorixafor inhibits CXCL12 binding and extracellular signal regulated kinase hyperactivation for CXCR4 mutations. Aims: To report on an early assessment of the safety and clinical response of mavorixafor in combination with ibrutinib after ≥6 months (6 cycles) of treatment in patients with MYD88 and CXCR4WHIM WM. Methods: This is an ongoing phase 1b, open-label, multicenter, single-arm study (NCT04274738) examining intrapatient dose escalation, safety, pharmacokinetics (PK), and pharmacodynamics of mavorixafor in combination with ibrutinib (target N=18). Eligibility includes age ≥18 years, clinicopathological WM diagnosis, consensus criteria indication for treatment, measurable disease, 0-3 prior therapies, and confirmed MYD88 and CXCR4WHIM mutations. Patients are initiated on mavorixafor 200 mg (low-dose) and ibrutinib 420 mg, both oral and once-daily. Mavorixafor escalation to 400 mg (mid-dose) occurs after 28 days if no dose-limiting toxicities (DLTs) are observed and to 600 mg (high-dose) after 400 mg is deemed safe (<2/6 DLTs). Patients are followed for adverse events (AEs), and change from baseline in IgM, Hgb, PK, WBC counts, and clinical responses. Results: At data cutoff of June 15, 2021, 10 patients have enrolled, with 9 dosed and 9 continuing on study. Both 200-mg and 400-mg mavorixafor doses in combination with ibrutinib were deemed safe. Dosing at 600 mg is ongoing. Median duration of treatment was 198 days. A total of 107 AEs were observed (79% grade 1). Of 92 AEs with complete assessment for causal relationship to study drugs, 9 were deemed related to mavorixafor only, 13 to ibrutinib only, and 18 to the combination. One DLT was observed, consisting of grade 3 hypertension attributed to combination therapy. Two grade 2 AEs attributed to mavorixafor only led to drug interruption (7-8 days). Overall response rate for evaluable patients (minor response or better) was 100% (N=8). Four of 8 patients achieved major response; 1 of 8 patients achieved very good partial response. All 9 patients showed decrease in serum IgM while on treatment, with IgM levels normalizing in 1 patient after 4 months' treatment. For all patients treated for ≥6 months (N=7), median absolute serum IgM level decreased to 31.04 g/L at 6 months from pretreatment level of 46.23 g/L . Mean Hgb increased by >20 g/L, with Hgb approaching normal levels in these 7 patients. Mavorixafor and ibrutinib exposures were consistent with previous reports (de Jong J, et al. Cancer Chemother Pharmacol. 2015;75(5):907-916), and combination treatment increased peripheral lymphocytes, neutrophils, and monocytes in all 9 patients. Conclusion: Our findings as of June 2021 in patients with WM carrying both MYD88 and CXCR4WHIM mutations show that mavorixafor in combination with ibrutinib is well tolerated. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug-drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. All evaluable patients demonstrated at least a minor response. Combination of mavorixafor with ibrutinib led to rapid, clinically meaningful, and durable decrease in IgM levels and increase in Hgb levels. These ongoing studies support the feasibility of combining ibrutinib with mavorixafor to improve responses in MYD88 CXCR4WHIM WM. Disclosures Treon: BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; Pharmacyclics: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; X4: Research Funding. Buske: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding. Thomas: Genentech: Research Funding; X4 Pharma: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Branagan: CSL Behring: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Gavriatopoulou: Genesis: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; GSK: Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garzon: X4 Pharmaceuticals: Consultancy. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Seyffert: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ali: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Tiwari, Kaushal Kishore, Silverio Sbrana, Stefano Bevilacqua, Paola Giungato, Angela Pucci, Filippo Santaerelli, Marco Solinas et Mattia Glauber. « Peripheral Blood Immunological Features Associated with Aortic Valve Disease and Ascending Throcic Aorta Aneurysm and Dilation ». Journal of Universal College of Medical Sciences 3, n^o 1 (3 septembre 2015) : 11–20. http://dx.doi.org/10.3126/jucms.v3i1.13252.

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INTRODUCTION: Ascending thoracic aortic aneurysm (TAA) is a multi-factorial process in which histological modifications and immune-mediated inflammation are closely associated. The predominant role of a Th1-mediated response in influencing aortic wall remodeling, dilation, and aneurysm formation has been suggested by previous studies. Recently, the importance of chemokine receptors for Th1 cells recruitment into vascular inflammatory sites, as well as of the balance between pro- and anti-inflammatory T-cell subsets in influencing the severity of coronary artery disease, have been described.MATERIAL AND METHODS: We evaluated activation markers and chemokine receptors expression on peripheral T-cell and NK cell subsets of subject with aortic valve disease associated with ascending TAA (ascending aortic diameter > 4 cm) and undergoing elective surgery for TAA (Group A), in comparison with patients with aortic valve disease without TAA (ascending aortic diameter < 4 cm) (Group B). Peripheral blood samples from the two groups were also compared for intracellular T-lymphocyte cytokine production, frequency of regulatory T cells (Treg) and soluble levels of cytokine and chemokines. The aortic size index (ASI) was considered a parameter able to reflect aortic pathophysiological modifications leading to aortic dilation.RESULTS: The results demonstrated correlations between ASI values and CCR5 expression on CD3+, CD3+/CD8+, CD4+ and CD4+/CD28- T-cell subsets. In Group A the expression of CCR5 was higher on CD3+/CD8+, CD4+ and CD4+/CD28- T-cell subsets, when compared with Group B. CD4+ and CD4+/CD28- T-cells in Group A showed also a higher expression for the co-stimulatory molecule CD28 and the activation marker CD25, respectively. An increased expression of CXCR3 was found on CD4+, CD3+/CD8+ and CD3+/TCR+ T-cell subsets in Group A. A higher circulating fraction of NK cells, together with a higher NK cell positivity for CX3CR1, were observed in aneurysmatic patients. Intracellular cytokine analysis demonstrated a higher fraction of CD3+/CD4+ T-cells producing IL-17A and IL-10 in Group A, together with a higher intracellular content for IL-21. Finally, a higher soluble level of fractalkine (CX3CL1) has been detected in aneurysm group.CONCLUSION: Results indicate a higher activation state, migratory capacity and cytotoxic potential of peripheral blood NK and T-cell subsets in patients with aortic valve disease associated with ascending TAA, when compared with patients affected by aortic valve disease alone. These findings, together with the observed higher polarization towards a Th17 in patients with aortic aneurysm could suggest the involvement of autoimmune mechanisms leading to cellular loss, inflammation and fibrosis during ascending aortic wall dilation and aneurysmatic progression.Journal of Universal College of Medical Sciences Vol. 3, No. 1, 2015: 11-20

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Ratajczak, Janina, Kasia Mierzejewska, Sylwia Borkowska, Magdalena Kucia et Mariusz Z. Ratajczak. « Novel Evidence That Human Umbilical Cord Blood-Purified CD133+ cells Secrete Several Soluble Factors and Microvesicles/Exosomes That Mediate Paracrine, Pro-Angiopoietic Effects Of These Cells – Implications For and Important Role Of Paracrine Effects in stem Cell Therapies In Regenerative Medicine ». Blood 122, n^o 21 (15 novembre 2013) : 1216. http://dx.doi.org/10.1182/blood.v122.21.1216.1216.

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Abstract Background Populations of CD34+, CD34+CXCR4+, and CD133+ cells are currently employed in the clinic to treat damaged organs (e.g., heart after myocardial infarction [AMI]). These cells are highly enriched, primarily for hematopoietic stem/progenitor cells (HSPCs), and for many years it has been wrongly supposed that HSPCs can trans-dedifferentiate into tissue-specific cells. However, even when improvement of organ function is observed after employing these cells in therapy, the lack of a convincing demonstration of significant donor-recipient chimerism in treated tissues in most of the studies performed indicates that mechanisms other than trans-dedifferentiation play a significant role in positive clinical outcomes. In support of this conclusion, we have already reported that CD34+ cells secrete a variety of growth factors, cytokines, chemokines, and bioactive lipids that interact with the surrounding microenvironment (Blood 2001;97:3075). Furthermore, microvesicles (MVs) or exosomes shed from the cell surface or derived from the intracellular membrane compartment (respectively) are important mediators in cell-to-cell communication and, as we demonstrated, may affect the biology of target cells by horizontal transfer of mRNA and proteins (Leukemia 2006;20:847). Hypothesis We hypothesized that some reported positive outcomes in adult stem cell therapies (e.g., when employing CD133+ cells) can be explained by the paracrine effects of these cells, involving both soluble factors as well as cell membrane-derived MVs. Experimental strategies CD133+ cells were purified from UCB (>95% purity as checked by FACS) and incubated for 24 hours in RPMI at 37°C in a small volume of medium supplemented with 0.5% albumin. Subsequently, we harvested conditioned media (CM) from these cells and isolated CD133+ cell-shed microvesicles (MVs) by high-speed centrifugation. We then employed sensitive ELISA assays to measure the concentration of important pro-angiopoietic and anti-apoptotic factors in CD133+ cell-derived CM and isolated mRNA from both CD133+ cells and CD133+ cell-derived MVs for RQ-PCR analysis of gene expression. Subsequently, the chemotactic activity of CD133+ cell-derived CM and MVs was tested against human UCB endothelial cells (HUVECs), and in parallel we tested whether CD133+ cell-derived CM and MVs induce major signaling pathways in HUVECs. Finally, in in vitro functional assays, we tested the ability of CD133+ cell-derived CM and MVs to induce tube formation by HUVECs and the ability of in vivo Matrigel assay implants to induce angiogenesis. Results We observed that highly purified UCB-derived CD133+ cells secrete several pro-angiopoietic factors (e.g., VEGF, KL, FGF-2, and IGF-1) into CM and shed microvesicles (MVs) from the cell surface and endosomal compartment that are enriched for mRNAs encoding VEGF, KL, FGF-2, and IGF-1. Both CD133+ cell-derived CM and MVs possessed anti-apoptotic properties, increased the in vitro cell survival of endothelial cells, stimulated phosphorylation of MAPKp42/44 and AKT in HUVECs, induced chemotactic migration, proliferation, and in vitro tube formation in HUVECs as well as stimulated in vivo angiogenesis in Matrigel implants. Conclusions Both in vitro and in vivo observations in animal models suggest that an important role for CD133+ cell-derived paracrine signals should be considered when evaluating clinical outcomes following the use of purified CD133+ cells in regenerative medicine. Overall, these cell-derived paracrine signals may explain the therapeutic benefits of adult stem cells employed in regeneration of, for example, heart following AMI. Finally, we will discuss several possibilities for enhancing secretion and modulating the composition of these paracrine signals, which could potentially be explored in the clinic. Disclosures: No relevant conflicts of interest to declare.

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Mierzejewska, Kasia, Magdalena Kucia, Janina Ratajczak et Mariusz Z. Ratajczak. « Novel Evidence for the Presence of Potent, Paracrine, Pro-Angiopoietic Effects of Purified Human Umbilical Cord Blood-Derived CD133+ Cells - Implications for Adult Stem Cell Therapies in Regenerative Medicine ». Blood 120, n^o 21 (16 novembre 2012) : 4740. http://dx.doi.org/10.1182/blood.v120.21.4740.4740.

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Abstract Abstract 4740 Background. As populations of CD34+, CD34+CXCR4+, or CD133+ cells that are enriched in stem cells, adult stem and progenitor cells purified from bone marrow (BM), mobilized peripheral blood (mPB), and umbilical cord blood (UCB) are currently employed in the clinic to treat damaged organs (e.g., heart after myocardial infarction [AMI] or injured spinal cord or liver). The cell populations expressing these phenotypes are highly enriched primarily for hematopoietic stem/progenitor cells (HSPCs) and small numbers of endothelial progenitors, and for many years it has been wrongly supposed that they can trans-dedifferentiate into tissue-specific cells. However, even when improvement of organ function is observed after employing them in therapy, the lack of a convincing demonstration for the presence of donor-recipient chimerism in treated tissues in most of the studies performed so far indicates that mechanisms other than trans-dedifferentiation of the HSPCs delivered to the damaged organs into tissue-specific cells play a significant role in some positive clinical outcomes. In support of this conclusion, evidence has accumulated that stem cells secrete a variety of growth factors, cytokines, chemokines, and bioactive lipids that interact with the surrounding microenvironment and, when used in therapy, improve cell viability in damaged organs. In particular, more attention is currently being paid to microvesicles (MVs), which are shed from the cell surface or derived from the intracellular membrane compartment as mediators in cell-to-cell communication. Hypothesis. We hypothesized that these positive outcomes in adult stem cell therapies (e.g., by employing CD133+ cells) can be explained by the paracrine effects of these cells, involving both soluble factors as well as cell membrane-derived MVs. Experimental strategies. CD133+ cells were purified from UCB by employing immunomagnetic beads (> 95% purity as checked by FACS) and incubated for 24 hours in RPMI at 37°C in a small volume of medium supplemented with 0.5% albumin. Subsequently, we harvested conditioned media (CM) from these cells and isolated CD133+ cell-shed microvesicles (MVs) by high speed centrifugation. We employed sensitive ELISA assays to measure the concentration of important pro-angiopoietic and anti-apoptotic factors in CD133+ cell-derived CM and isolated mRNA from both CD133+ cells and CD133+ cell-derived MVs for RQ-PCR analysis of gene expression. Subsequently, the chemotactic activity of CD133+ cell-derived CM and MVs was tested against human umbilical cord blood endothelial cells (HUVECs), and, in parallel, we tested whether CD133+ cell-derived CM and MVs induce major signaling pathways in HUVECs. Finally, in in vitro functional assays, we tested the ability of CD133+ cell-derived CM and MVs to induce tube formation by HUVECs and the ability of in vivo Matrigel assay implants to induce angiogenesis. Results. We observed that highly purified UCB-derived CD133+ cells express mRNAs and secrete proteins for several pro-angiopoietic factors (e.g. VEGF, KL, FGF-2, and IGF-1) into CM and shed microvesicles (MVs) from the cell surface and endosomal compartment that are enriched for mRNAs encoding VEGF, KL, FGF-2, and IGF-1. Both CD133+ cell-derived CM and MVs possessed anti-apoptotic properties, increased the in vitro cell survival of endothelial cells, stimulated phosphorylation of MAPKp42/44 and AKT in HUVECs, induced chemotactic migration, proliferation and tube formation in vitro in HUVECs, as well as stimulated in vivo angiogenesis in Matrigel implants. Conclusions. These observations suggesting an important role for CD133+ cell-derived paracrine signals should be considered when evaluating clinical outcomes using purified CD133+ cells in regenerative medicine. Overall, these cell-derived paracrine signals may explain the therapeutic benefits of adult stem cells employed in regeneration of, for example, heart AMI. Finally, we will discuss several possibilities for enhancing secretion and modulating the composition of these paracrine signals that could be explored in the clinic. Disclosures: No relevant conflicts of interest to declare.

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Shastri, Aditi, Ira Braunschweig, Stefan Klaus Barta, Noah Kornblum, Olga Derman, Ramakrishna Battini, Amit Verma, Paul S. Frenette et Murali Janakiram. « Stimulation of Adrenergic Activity By Desipramine Enhances Hematopoietic Stem and Progenitor Cell Mobilization Along with G-CSF in Multiple Myeloma - a Pilot Study of Safety and Efficacy ». Blood 126, n^o 23 (3 décembre 2015) : 3101. http://dx.doi.org/10.1182/blood.v126.23.3101.3101.

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Abstract Background: Hematopoietic stem cell release is regulated by the sympathetic nervous system through the β (3) adrenergic receptor [Mendez-Ferrer et al. Nature 2008]. Peripheral sympathetic nerve neurons express the G-CSF receptor and stimulation of peripheral sympathetic nerve neurons with G-CSF reduced norepinephrine (NE) reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability [Lucas et al Blood 2012]. Based on preclinical data, we investigated the NE reuptake inhibitor desipramine in HSC mobilization. Despite augmentation with Plerixafor (CXCR4 inhibitor), 20% of all patients fail to mobilize 6*10^6 CD34 cells/kg in myeloma and the collection rate with G-CSF alone is 51.1% [Diperiso et al Blood 2012]. The cost of upfront plerixafor is $9,081 per patient while desipramine costs $40. We undertook a feasibility study of adult patients with MM undergoing autologous transplantation (ASCT) to study safety and efficacy of mobilization with desipramine and G-CSF. Patients & Methods: From 2013- 2014, 10 patients between the ages of 18-70, eligible for ASCT were enrolled. Desipramine 100mg daily was administered for 7 days, starting 4 days prior to starting G-CSF (D-3) and continue along with G-CSF for a total of 7 days. CBC and CD34 counts were determined on Day+5. If CD34 counts were > 10/ul, stem cell collection was commenced and if < 10/ul, plerixafor was added as salvage therapy. The endpoints were safety and efficacy in mobilizing CD34 cells for ASCT in patients with multiple myeloma. This trial was registered at clinicaltrials.gov as NCT01899326. Results Six of ten patients enrolled completed the protocol and underwent stem cell transplantation. Reasons for not completing were 1. Lack of insurance coverage 2. Non-compliance with study treatment 3. Disease relapse prior to ASCT. Five patients did not have any grade 3 or 4 adverse events and 1 had disease-related Grade 4 hypercalcemia and Grade 2 AKI at the time of stem cell mobilization. No patients had significant treatment related adverse effects. All 6 patients who completed the protocol achieved the target collection of 5*10^6 CD34 cells/kg. Four patients achieved 6*10^6 CD34 cells/kg or more and the remaining 2 patients achieved 5.52 and 5.92 *10^6 CD34 cells/kg respectively. Among the 6 patients, 2 patients received salvage plerixafor. The median time to achieve WBC >1000/ul, ANC >500/ul and platelets>20k was 11.5, 11, 13.5 days Table 1. Age Ind. Regimne Disease status P PB CD34/ul CD34 collected *10^6 / kg Total CD34/kg collected Engraftment (Days to) Adverse effects from desipramine D1 D2 D3 D4 D2 D3 D4 ANC >0.5 Platelets> 20k G1,G2 G3,G4 1 62 Free λ VRD VGPR N 45.8 66.0 7.01 7.01 12 13 none none 2 50 Free λ VRD VGPR N 88.0 143.5 12.22 12.22 12 12 none none 3 58 IgA VCD VGPR N 38.0 67.7 31.6 4.22 2.75 6.97 13 17 none none 4 70 IgAκ VRD VGPR Y 2.40 40.2 16.6 4.31 1.61 5.92 12 14 none none 5 56 IgGκ VCD VGPR Y 8.70 11.9 37.1 19.4 1.33 4.57 1.61 7.51 11 12 none none 6 70 IgGλ VD RD Relapse N 76.2 97.1 5.54 5.54 11 20 AKI hypercalcemia P-Plerixafor; V-Velcade; R-Lenalidomide; D-Dexamethasone; C-Cyclophosphamide Conclusions Overall G-CSF + Desipramine combination appears to be safe, well tolerated and shows signs of efficacy. G-CSF and desipramine was successful in 4/6 (66%) and all achieved the stem cell collection in 2 days or less. Desipramine, GCSF and Plerixafor was successful in all (6/6) patients to achieve a target of 5*10^6 CD34 cells/kg. The mean number of CD34 cells collected in the desipramine+ G-CSF mobilisers was 7.24*10^6 CD34 cells/kg which, based on historical data, is higher than what would be expected with G-CSF alone even though 3/4 of these patients had lenalidomide as induction therapy. Based on these results, a phase II clinical study evaluating the efficacy of G-CSF with desipramine with or without salvage plerixafor in multiple myeloma and lymphoma will be initiated. Disclosures Barta: Seattle Genetics: Research Funding.

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Sasajima, Junpei, Toru Kawamoto, Yoshiaki Sugiyama, Yusuke Mizukami, Yasuyuki Iuchi, Toshifumi Ashida, Hiroki Tanabe, Yoshihiro Torimoto et Yutaka Kohgo. « Increased Angiogenic Property Of Human Peripheral Blood Monocytes By ex Vivo Culture With c-Mpl Agonists In Hindlimb Ischemia Mouse Model ». Blood 122, n^o 21 (15 novembre 2013) : 1062. http://dx.doi.org/10.1182/blood.v122.21.1062.1062.

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Abstract Human peripheral blood mononuclear cells (PB-MNCs) include some populations which have angiogenic properties. Pro-angiogenic monocytes from PB-MNCs are considered as one of candidates for angiogenic therapy in regenerative medicine. Indeed, in a recent German clinical post-infarction remodeling study (TOPCARE-AMI) for ischemic heart disease, the ex vivo culture of PB-MNCs was employed. However, in this trial, there were different therapeutic efficacies in each case, possibly due to the different expansion efficacy of the ex vivo culture of PB-MNCs using autologous serum. In order to resolve this issue, we developed a new serum-free culture system composed of X-VIVO15 medium supplemented with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Floating spheres obtained by this serum-free culture system were mainly composed of CD11b+ monocytes. Interestingly, the mRNA expression of c-Mpl (thrombopoietin receptor) was markedly elevated compared with PB-MNCs, suggesting c-Mpl agonist could increase angiogenic property of cultured CD11b+ monocytes. Therefore, we assessed the impact of c-Mpl agonists on PB-MNC cultures in our serum-free method composed of X-VIVO15 medium with VEGF and bFGF. Both recombinant human thrombopoietin (rHuTPO) and romiplostim, a clinical grade second-generation TPO-receptor agonist, successfully increased sphere formations regarding both the number and size. The expressions of angiogenic factors, IL-8, CXCR4, and vasohibin-2, mRNA of CD11b+ monocytes cultured with c-Mpl agonists were up-regulated, indicating that cultivated CD11b+ monocytes have a proangiogenic potential. Finally, we investigated the proangiogenic potential of PB-MNCs derived CD11b+ monocytes in a hindlimb ischemia model utilizing BALB/c nude mice. Mice were randomly assigned to 7 groups: control mouse group (PBS-injected), freshly isolated CD11b+ monocyte-injected mouse group, cultivated CD11b+ monocyte with 2ng/ml and 20ng/ml rHuTPO -injected mouse groups, cultivated CD11b+ monocyte with 100ng/ml and 1000ng/ml romiplostim -injected mouse groups, cultivated CD11b+ monocyte without rHuTPO and romiplostim -injected mouse group. The intramuscular injection of CD11b+ monocytes cultivated with 20 ng/ml rHuTPO into the ischemic limb completely rescued the limbs from auto-amputations or foot necrosis, while only one (10.0%) of the control mice could be rescued. In addition, the intramuscular injection of both freshly isolated CD11b+ monocytes and CD11b+ monocytes cultivated without rHuTPO and romiplostim had a weak rescue effect on the ischemic limbs (8 and 7 of 10 mice had auto-amputations or foot necrosis, respectively). The salvage rate from necrosis in cultivated CD11b+ monocyte with romiplostim-injected mouse group is also superior to that in cultivated CD11b+ monocyte without rHuTPO-injected mouse group. Analysis of blood perfusion by a laser Doppler perfusion imaging system showed a significantly higher recovery in mice receiving the CD11b+ monocytes cultivated with 2 ng/ml or 20 ng/ml rHuTPO or 100ng/ml romiplostim 1 week after surgery. The functional capillary density and surface area visualized by perfusion with BS-I lectin also significantly increased in the rHuTPO- or romiplostim-treated group. In conclusion, an ex vivo addition of c-Mpl agonists augmented the pro-angiogenic activity of peripheral CD11b+ monocytes, and this method would be promising for human cell therapy to induce vascular regeneration by activating the angiogenic property in human peripheral blood-derived monocytes. Disclosures: Mizukami: The New Energy and Industrial Technology Development Organization of Japan: Research Funding.

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Sayed, Afreen Asif Ali, David Standing, Prasad Dandawate, Shahid Umar, Roy Jensen, Rahul Parikh, John Taylor et Shrikant Anant. « Abstract 2558 : Determining the expression of RNA binding protein Rbm3 in tumor cells and immune cells in the tumor microenvironment in prostate cancer ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 2558. http://dx.doi.org/10.1158/1538-7445.am2022-2558.

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Abstract Prostate cancer is the most common cancer among men. Currently, targeting the AR pathway, chemotherapy or immune-based therapies are major options but only provide a modest improvement in overall survival. RNA binding proteins have been shown to regulate AR expression in the progression of PCa. We and others have demonstrated that RNA binding protein RBM3 is upregulated in various solid tumors including PCa. We have also shown that RBM3 binds to 3’UTR of mRNAs of tumor-promoting factors and increases their mRNA stability and translation. However, the role of RBM3 in PCa is not well evaluated. We first analyzed the expression levels of RBM3 in the TCGA database. There was a significant increase in RBM3 expression even in cancers with a Gleason score of 6 upto Gleason 10 cancers. To confirm this we performed RT-PCR analyses of a prostate cancer cDNA panel. There was a significant increase in RBM3 expression in the PCa tissues compared to normal control. We used LNCaP and its derivative cell line C4-2B which show features of progressed disease such as metastatic capability and hormone independence. RT-PCR and western blot analyses demonstrated significantly higher RBM3 levels in C4-2B cells as compared to LNCaP cells suggesting a role for RBM3 in tumor progression. The tumor microenvironment also plays a very important role in prognosis of PCa. Specifically, tumor-associated macrophages (TAMs) have been shown to increase metastatic potential and increase tumor angiogenesis. To determine the levels of RBM3 expression and its effects on macrophage infiltration, we mined the TCGA database using TIMER2.0 software. There was a positive correlation of RBM3 expression with infiltration of both M1 and M2 macrophages. To further study the effect of interactions between PCa cells and TAMs, we used immortalized THP1 monocytes, which can be activated to M1 and M2 macrophages. We observed that just converting the THP1 cells to M1 or M2 macrophages increased RBM3 expression in both cell types. Also, when M1 and M2 macrophages were treated with conditioned media from LNCaP or C4-2B cells, there was an induction in the expression of RBM3. Similarly, when conditioned media from M0, M1, M2 activated THP1 cells were applied to LNCaP and C4-2B cells, there was an increase in RBM3 expression in the PCa cells. This suggests a positive cross-talk between the macrophages and PCa cells. We evaluated the cytokine profile in the conditioned media from M1 and M2 macrophages and determined that while M1 macrophages had increased levels of CXCL10, M2 macrophages showed higher levels of IL4 and IL10. Moreover, PCa cells have higher levels of CXCR3, the receptor for CXCL10. Together, these data suggest that crosstalk between TAMs and cancer cells in the PCA microenvironment plays a significant role in increasing RBM3 expression, which in turn enhances global translation of disease progression related genes. Citation Format: Afreen Asif Ali Sayed, David Standing, Prasad Dandawate, Shahid Umar, Roy Jensen, Rahul Parikh, John Taylor, Shrikant Anant. Determining the expression of RNA binding protein Rbm3 in tumor cells and immune cells in the tumor microenvironment in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2558.

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Wagar, Lisa E., Brian Sworder, Michael S. Khodadoust, Mark M. Davis et Ash A. Alizadeh. « Follicular Lymphoma Organoids for Investigating the Tumor Microenvironment ». Blood 134, Supplement_1 (13 novembre 2019) : 2799. http://dx.doi.org/10.1182/blood-2019-131192.

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Background: Current in vitro lymphoma models, including three-dimensional organoids, generally contain exclusively neoplastic lymphocytes and require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of syngeneic tumor-infiltrating lymphocytes (TILs) alongside endogenous primary malignant lymphocytes could be useful for modeling complex interactions in the TME, and for immunological maneuvers and therapies relying on TILs. However, such conditions for maintaining lymphomas in their syngeneic TME as a cohesive unit have remained elusive. Methods: We adapted an air-liquid interface (ALI) method that we previously described (Neal JT et al 2019 Cell) for propagating patient-derived organoids (PDOs) from primary human follicular lymphomas. Surgically excised lymphoma samples were tested for the ability to maintain lymphoma cell viability in vitro using a lymph node organoid technique. Lymph nodes containing lymphoma cells (and in one case, a PBMC sample including circulating lymphoma cells) were processed into a single cell suspension and frozen until use. Samples were thawed and prepared into immune organoids (see figure). We assessed cell composition by flow cytometry on day 7, and in a subset of samples, up to 21 days post-thaw. Results: A total of 6 patients were profiled for PDO formation, PDO composition and stability, and PDO longevity. 4 of 6 samples showed good cell viability at day 7 post-culture and in a subset of samples, up to 21 days post-culture. Cell composition was well-maintained over time, with presence of lymphoma cells (CD19+ CD10+ CD5-) easily detectable and maintenance of supporting cells of the lymph node such as T follicular helper cells (CD3+ CD4+ CXCR5+ PD-1+) and non-B, non-T cells. Supporting lymph node cells were not detected in the PBMC sample, suggesting the cell composition is related to the initial composition and not due to differentiation in vitro. Genotyping, gene expression phenotyping, and T-cell/B-cell receptor profiling data will be presented at the meeting, including accuracy of PDOs for preserving the original spectrum of these indices. Conclusions: Propagation of PDOs of primary lymphomas with endogenous immune stroma is feasible and maintains cohesive elements of the TME. This system should allow immunoncology investigations within the TME and to facilitate personalized immunotherapy testing. Fig 1: Human lymphoma organoid cultures as a model to study tumor microenvironments and immune responses in vitro. (A) Experimental schema for preparing lymphoma organoids from tumor explants. In an adapted workflow optimized for ex vivo culture of human tonsillar germinal centers (Wagar L et al, submitted), we subject cryopreserved FL samples to organoid culture. (B) An example of follicular lymphoma organoid reorganization in vitro after four days in culture. (C) Total cell viability in FL organoids for up to 21 days in culture. Six samples were tested. (D) Frequency of major cell types in FL samples after organoid culture. Although there is variation among donors' samples, an individual's cell composition is well maintained for at least 14 days in most organoids. Figure 1 Disclosures Khodadoust: Corvus Pharmaceuticals: Research Funding. Davis:Vir Biotechnology: Consultancy, Equity Ownership, Honoraria; PACT Bio: Consultancy, Equity Ownership, Honoraria; Adicet Inc: Consultancy, Equity Ownership, Honoraria; Chuga Pharmabody: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Atreca: Consultancy, Equity Ownership, Honoraria; Juno: Consultancy, Equity Ownership, Honoraria. Alizadeh:Pfizer: Research Funding; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Roche: Consultancy.

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Pouzol, Laetitia, Anna Sassi, Nadège Baumlin, Mélanie Tunis, Daniel S. Strasser, François Lehembre et Marianne M. Martinic. « CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis ». Frontiers in Pharmacology 12 (5 novembre 2021). http://dx.doi.org/10.3389/fphar.2021.748740.

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Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.

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Xing, Dongqi, Fadi G. Hage, Wenguang Feng, Yuanyuan Guo, Suzanne Oparil et Paul W. Sanders. « Endothelial Cells Overexpressing CXCR1/2 are Renoprotective in Rats with Acute Kidney Injury ». American Journal of Physiology-Renal Physiology, 16 février 2023. http://dx.doi.org/10.1152/ajprenal.00238.2022.

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Inflammation that develops with the release of chemokines and cytokines during acute kidney injury (AKI) has been shown to participate in functional renal recovery. While a major research focus has been on the role of macrophages, the family of CXC motif chemokines that promote neutrophil adherence and activation also increase with kidney ischemia/reperfusion (I/R) injury. This study tested the hypothesis that intravenous delivery of endothelial cells that overexpress CXCR1 and CXCR2 improves outcomes in kidney I/R injury. Overexpressing CXCR1/2 enhanced homing of ECs to I/R-injured kidneys and limited interstitial fibrosis, capillary rarefaction and tissue injury biomarkers (serum creatinine concentration and urinary KIM-1) following AKI and also reduced expression of P-selectin, the rodent CXC motif chemokine, CINC-2β, and the number of MPO-positive cells in the post-ischemic kidney. The serum chemokine/cytokine profile, including CINC-1, showed similar reductions. These findings were not observed in rats given endothelial cells transduced with empty adenoviral vector (Null-EC) or vehicle alone. These data indicate that extrarenal endothelial cells that overexpress CXCR1 and CXCR2, but not Null-EC or vehicle alone, reduce I/R kidney injury and preserve kidney function in a rat model of AKI.

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Zhang, Yali, Michele Esposito, Xiaoying Qiao, Vikram Paruchuri, Emily Mackey, Kevin Morine, Gavin Schnitzler et al. « Abstract 452 : Primary Left Ventricular Unloading Reduces Infarct Size by Increasing Myocardial Levels of Stromal Derived Factor One Alpha (SDF1a) in Acute Myocardial Infarction ». Circulation Research 121, suppl_1 (21 juillet 2017). http://dx.doi.org/10.1161/res.121.suppl_1.452.

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Stromal derived factor 1 alpha (SDF1a) is a constitutively expressed cardioprotective chemokine that is rapidly degraded by proteases. We reported that compared to Primary Reperfusion (PR), first reducing myocardial oxygen demand by activating a trans-valvular pump (Impella CP) while delaying coronary reperfusion (Primary Unloading; PU) reduces infarct size in acute myocardial infarction (AMI). We now hypothesize that PU reduces proteolytic degradation of SDF1a thereby increasing SDF1a signaling via the receptor CXCR4 in AMI. Methods: AMI was induced by occlusion of the left anterior descending artery (LAD) for 90 min in male swine (n=4/group). In the PR group, the LAD was reperfused for 120 min. In the PU group, after 90 min of ischemia an Impella CP was activated and the LAD left occluded for an additional 30 min, followed by 120 min of reperfusion. Whole-transcript expression analysis was performed on RNA from the infarct zone using Porcine 1.0 ST microarrays and ConsensusPathDB programs. Quantitative polymerase chain reaction, western blots, and activity assays determined expression and activity of the SDF1a signaling pathway. Sham operated LV samples served as controls. Results: Compared to PR, PU reduced fibrotic and inflammatory gene expression including reduced transcript levels of matrix-metalloprotease-2 (MMP2), MMP9 and dipeptidyl peptidase-4 (DPP4). Compared to PR, PU increased SDF1a protein levels within the infarct zone. Gel zymography confirmed reduced activity levels of MMP2 and MMP9 within the infarct zone after PU, not PR. Compared to PR, PU attenuated DPP4 protein levels and activity and protein levels of CXCR7, an SDF1a sequestration receptor, within the infarct zone. To explore a functional role for SDF1a in PU, adult male swine received intra-coronary injections of AMD3100, a CXCR4 receptor antagonist, after Impella CP activation. Loss of CXCR4 activity attenuated cardioprotective signaling via Akt, Erk and GSK3b and increased infarct size compared to vehicle treated controls. Conclusion: We introduce a novel mechanism by which PU limits proteolytic degradation and CXCR7 mediated sequestration of SDF1a, thereby increasing cardioprotective signaling via SDF1a and overcoming a critical barrier to SDF1a therapeutics in AMI.

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Chang, Huang-Ming, Kang-Yung Peng, Chieh-Kai Chan, Chiao-Yin Sun, Ying-Ying Chen, Han-Mei Chang, Chun-Lin Huang et al. « FGF23 ameliorates ischemia-reperfusion induced acute kidney injury via modulation of endothelial progenitor cells : targeting SDF-1/CXCR4 signaling ». Cell Death & ; Disease 12, n^o 5 (17 avril 2021). http://dx.doi.org/10.1038/s41419-021-03693-w.

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AbstractThe levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

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Huang, Rong-zhi, Jie Zheng, Feng-ling Liu, Qing-ling Li, Wen-hui Huang, Dan-meng Zhang et Qiang-chu Wu. « A Novel Autophagy-Related Marker for Improved Differential Diagnosis of Rheumatoid Arthritis and Osteoarthritis ». Frontiers in Genetics 12 (12 octobre 2021). http://dx.doi.org/10.3389/fgene.2021.743560.

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Rheumatoid arthritis (RA) and osteoarthritis (OA) are two most common rheumatic diseases in the world. Although there are standard methods for the diagnosis of both RA and OA, the differentials in some cases are poor. With deepening research, the role of autophagy in maintaining cell homeostasis and thus enabling cells adapt to external environments has become increasingly prominent. Both RA and OA, two diseases with inherent differences in pathogenesis, gradually show differences in autophagy levels. Our study therefore aims to further understand differences in pathogenesis of RA and OA through in-depth studies of autophagy in RA and OA. We also define appropriate autophagy-related markers as recognition indicators. Differences in autophagy levels between RA and OA were found based on analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and single-sample gene set enrichment (ssGSEA). These differences were mainly caused by 134 differentially expressed genes (DEGs). In two autophagy-related genes, CXCR4 and SERPINA1, there existed significant statistical difference between RA and OA. An autophagy related index (ARI) was thus successfully constructed based on CXCR4 and SERPINA by binary logistic regression of the generalized linear regression (GLR) algorithm. Pearson analysis indicated that the expression of CXCR4, SERPINA1, and ARI were closely correlated with autophagy scores and immune infiltration. Moreover, ARI showed high disease identification through receiver operating characteristic (ROC) analysis (AUCtesting cohort = 0.956, AUCtraining cohort = 0.867). These results were then verified in GSE12021 independent cohort. In conclusion, ARI associated with autophagy and immune infiltration was successfully constructed for accurately identifying OA and RA. The index, thus, has great potential in clinical applications.

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Tang, Yao Liang, Leping Shen, Keping Qian et M. Ian Phillips. « Abstract 859 : Hypoxia-activated CXCR4 Expression In Cardiac Progenitor Cells For Replenishing Stem Cell Pool In Acute Ischemic Myocardium ». Circulation 116, suppl_16 (16 octobre 2007). http://dx.doi.org/10.1161/circ.116.suppl_16.ii_167-c.

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The resident cardiac progenitor cells (CPCs) have been identified in the adult myocardium, however, the CPC pool is rapidly depleted after acute myocardial infarction (AMI). The strategy to home ex vivo cultured CPCs to ischemic myocardium might be an important strategy to replenish resident CPC pool, and improve cardiac function. The CXC chemokine SDF-1α and its receptor CXCR4 have been identified as critical mediator for the ischemia-specific recruitment of progenitor cells, yet the level of CXCR4 expression in CPCs is quite low in normal conditions. Our previous studies showed that hypoxia can optimize CPCs via inducing functional CXCR4 expression in vitro, therefore, in this study, we want to investigate whether the transplantation of hypoxia treated CPCs (Hypo:CPCs) have the benefit of improving cardiac function resulted from increased cell homing in ischemic myocardium through mechanisms of hypoxia induced CXCR4 expression. To compare the homing capability between CPCs and Hypo:CPCs in response to endogenous SDF-1 signal in acute ischemic myocardium, we used retrovirus (pCL-MFG-β-gal) to label c-kit + Lin − CPCs with β-gal, and then injected labeled CPCs and Hypo:CPCs (1×10 6 ) intravenously via intra-jugular vein to mice 10 min after induction of MI in the C56BL/6 mice. We harvested the hearts 1d after cell transplantation to quantify the cell retention by chemiluminescent β-galactosidase assay. We observed that hypoxia treatment resulted in about 2.5 fold increase in β-gal cell recruitment in ischemic hearts (p<0.001, n=7– 8/group), however, AMD3100 can partially reduce Hypo:CPCs homing, therefore, the beneficial effects of Hypo:CPCs transplantation were mediated primarily through increasing cell homing via SDF-1:CXCR4 binding within the ischemic hearts. In addtion, the infusion of Hypo:CPCs also led to improved left ventricular performance, as assessed by LV development pressure by Millar catheter, by 23.67% compared with CPCs at 1 month after cell therapy (p<0.001, n=6/group). These results indicate that replenish CPC pool after AMI using ex vivo cultured CPC transplantation has significant beneficial effects on injured heart function dependent of hypoxia induced CXCR4 upregulation.

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He, Guo-dong, Yu-qing Huang, Lin Liu, Jia-yi Huang, Kenneth Lo, Yu-ling Yu, Chao-lei Chen, Bin Zhang et Ying-qing Feng. « Association of Circulating, Inflammatory-Response Exosomal mRNAs With Acute Myocardial Infarction ». Frontiers in Cardiovascular Medicine 8 (19 août 2021). http://dx.doi.org/10.3389/fcvm.2021.712061.

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Background: Although many cardiovascular disease studies have focused on the microRNAs of circulating exosomes, the profile and the potential clinical diagnostic value of plasma exosomal long RNAs (exoLRs) are unknown for acute myocardial infarction (AMI).Methods: In this study, the exoLR profile of 10 AMI patients, eight stable coronary artery disease (CAD) patients, and 10 healthy individuals was assessed by RNA sequencing. Bioinformatic approaches were used to investigate the characteristics and potential clinical value of exoLRs.Results: Exosomal mRNAs comprised the majority of total exoLRs. Immune cell types analyzed by CIBERSORT showed that neutrophils and monocytes were significantly enriched in AMI patients, consistent with clinical baseline values. Biological process enrichment analysis and co-expression network analysis demonstrated neutrophil activation processes to be enriched in AMI patients. Furthermore, two exosomal mRNAs, ALPL and CXCR2, were identified as AMI biomarkers that may be useful for evaluation of the acute inflammatory response mediated by neutrophils.Conclusions: ExoLRs were assessed in AMI patients and found to be associated with the acute inflammatory response mediated by neutrophils. Exosomal mRNAs, ALPL and CXCR2, were identified as potentially useful biomarkers for the study of AMI.

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WANG, H., Y. J. YANG, H. Y. QIAN, Q. ZHANG, L. J. GAO, P. LI, T. J. WANG et S. D. WANG. « Statin Administration Does Not Improve the Mobilization of Very Small Embryonic-Like Stem Cells (VSELs) in Contrast to Resveratrol Treatment in a Murine Model of Acute Myocardial Infarction ». Physiological Research, 17 octobre 2012, 543–49. http://dx.doi.org/10.33549/physiolres.932390.

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We have found that short-term statin treatment plus stem cell transplantation in acutely infarcted hearts improves cardiac function because statins promote the efficacy of cellular cardiomyoplasty. Autologous Sca-1+Lin-CD45-(CXCR+) very small embryonic-like stem cell (VSEL) mobilization in acute myocardial infarction (AMI) correlates with the preservation of cardiac function. Whether short-term atorvastatin (Ator) can enhance the mobilization or recruitment of VSELs in AMI is still unclear. We divided mice into 4 groups: 1) sham; 2) AMI; 3) AMI+resveratrol (RSV) as a positive control; and 4) AMI+Ator. There was an increase in the circulating VSEL/full population of leukocytes (FPL) ratio 48 hours after AMI, and AMI+RSV increased it further. Ator administration did not increase the VSEL/FPL ratio. The cardiac stromal cell-derived factor-1 (SDF-1) and SDF-1α levels were in agreement with the results of VSEL mobilization. One week after AMI, more Sca-1+CXCR+ cells were recruited to the myocardium of AMI+RSV mice but not AMI+Ator mice. Short-term Ator administration failed to upregulate cardiac SDF-1 and could not enhance the recruitment of VSELs early after AMI.

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Jeong, Han Saem, Jong-ho Kim et Soon Jun Hong. « Abstract P1027 : Cardioprotective Effects Of Genetically Engineered Cardiac Stem Cells By Spheroid Formation On Ischemic Cardiomyocytes ». Circulation Research 131, Suppl_1 (5 août 2022). http://dx.doi.org/10.1161/res.131.suppl_1.p1027.

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Background: Sca-1+ cardiac stem cells and their limited proliferative potential were major limiting factors for use in various studies. Methods: Therefore, the effects of sphere genetically engineered cardiac stem cells (S-GECS) inserted with telomerase reverse transcriptase (TERT) were investigated to examine cardiomyocyte survival under hypoxic conditions. GECS was obtained from hTERT-immortalized Sca-1+ cardiac stem cell (CSC) lines, and S-GECS were generated using poly-HEMA. Results: The optimal conditions for S-GECS was determined to be 1,052 GECS cells/mm 2 and a 48 hours culture period. Compared to adherent-GECS (A-GECS) and S-GECS showed significantly higher mRNA expression of the growth factors SDF-1α and CXCR4. S-GECS conditioned medium (CM) significantly reduced the proportion of early and late apoptotic cardiomyoblasts during CoCl 2 -induced hypoxic injury; however, gene silencing via CXCR4 siRNA deteriorated the protective effects of S-GECS against hypoxic injury. As downstream pathways of SDF-1α/CXCR4, the Erk and Akt signaling pathways were stimulated in the presence of S-GECS CM. S-GECS transplantation into a rat acute myocardial infarction model improved cardiac function and reduced the fibrotic area. These cardioprotective effects were confirmed to be related with the SDF-1α/CXCR4 pathway. Conclusions: Our findings suggest that paracrine factors secreted from transplanted cells may protect host cardiomyoblasts in the infarcted myocardium, contributing to beneficial left ventricle (LV) remodeling after acute myocardial infarction (AMI).

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« P31 : CXCR4-expressing myeloid-derived suppressor cells are essential to promote feto-maternal immunotolerance ». American Journal of Reproductive Immunology 80 (juin 2018) : 71–72. http://dx.doi.org/10.1111/aji.30_12984.

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