Articles de revues sur le sujet « Acute Kidney Injury, Tubular Progenitor, Tubular regeneration, Stem Cells »
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Maeshima, Akito, Shunsuke Takahashi, Masao Nakasatomi et Yoshihisa Nojima. « Diverse Cell Populations Involved in Regeneration of Renal Tubular Epithelium following Acute Kidney Injury ». Stem Cells International 2015 (2015) : 1–8. http://dx.doi.org/10.1155/2015/964849.
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Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. Surviving tubular cells actively proliferate, migrate, and differentiate in the kidney regeneration process after injury, and some cells express putative stem cell markers or possess stem cell properties. Using fate mapping techniques, bone marrow-derived cells and endothelial progenitor cells have been shown to transdifferentiate into tubular components in vivo or ex vivo. Similarly, it has been demonstrated that, during tubular cell regeneration, several inflammatory cell populations migrate, assemble around tubular cells, and interact with tubular cells during the repair of tubular epithelium. In this review, we describe recent advances in understanding the regeneration mechanisms of renal tubules, particularly the characteristics of various cell populations contributing to tubular regeneration, and highlight the targets for the development of regenerative medicine for treating kidney diseases in humans.
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Ciarambino, Tiziana, Pietro Crispino et Mauro Giordano. « Gender and Renal Insufficiency : Opportunities for Their Therapeutic Management ? » Cells 11, no 23 (29 novembre 2022) : 3820. http://dx.doi.org/10.3390/cells11233820.
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Acute kidney injury (AKI) is a major clinical problem associated with increased morbidity and mortality. Despite intensive research, the clinical outcome remains poor, and apart from supportive therapy, no other specific therapy exists. Furthermore, acute kidney injury increases the risk of developing chronic kidney disease (CKD) and end-stage renal disease. Acute tubular injury accounts for the most common intrinsic cause of AKI. The main site of injury is the proximal tubule due to its high workload and energy demand. Upon injury, an intratubular subpopulation of proximal epithelial cells proliferates and restores the tubular integrity. Nevertheless, despite its strong regenerative capacity, the kidney does not always achieve its former integrity and function and incomplete recovery leads to persistent and progressive CKD. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism in renal injury and opportunities for therapeutic manipulation, with a focus on resident renal progenitor stem cells as potential novel therapeutic strategies.
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Maeshima, Akito, Masao Nakasatomi et Yoshihisa Nojima. « Regenerative Medicine for the Kidney : Renotropic Factors, Renal Stem/Progenitor Cells, and Stem Cell Therapy ». BioMed Research International 2014 (2014) : 1–10. http://dx.doi.org/10.1155/2014/595493.
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The kidney has the capacity for regeneration and repair after a variety of insults. Over the past few decades, factors that promote repair of the injured kidney have been extensively investigated. By using kidney injury animal models, the role of intrinsic and extrinsic growth factors, transcription factors, and extracellular matrix in this process has been examined. The identification of renal stem cells in the adult kidney as well as in the embryonic kidney is an active area of research. Cell populations expressing putative stem cell markers or possessing stem cell properties have been found in the tubules, interstitium, and glomeruli of the normal kidney. Cell therapies with bone marrow-derived hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, and amniotic fluid-derived stem cells have been highly effective for the treatment of acute or chronic renal failure in animals. Embryonic stem cells and induced pluripotent stem cells are also utilized for the construction of artificial kidneys or renal components. In this review, we highlight the advances in regenerative medicine for the kidney from the perspective of renotropic factors, renal stem/progenitor cells, and stem cell therapies and discuss the issues to be solved to realize regenerative therapy for kidney diseases in humans.
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Osafune, Kenji. « iPSC technology-based regenerative medicine for kidney diseases ». Clinical and Experimental Nephrology 25, no 6 (3 mars 2021) : 574–84. http://dx.doi.org/10.1007/s10157-021-02030-x.
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AbstractWith few curative treatments for kidney diseases, increasing attention has been paid to regenerative medicine as a new therapeutic option. Recent progress in kidney regeneration using human-induced pluripotent stem cells (hiPSCs) is noteworthy. Based on the knowledge of kidney development, the directed differentiation of hiPSCs into two embryonic kidney progenitors, nephron progenitor cells (NPCs) and ureteric bud (UB), has been established, enabling the generation of nephron and collecting duct organoids. Furthermore, human kidney tissues can be generated from these hiPSC-derived progenitors, in which NPC-derived glomeruli and renal tubules and UB-derived collecting ducts are interconnected. The induced kidney tissues are further vascularized when transplanted into immunodeficient mice. In addition to the kidney reconstruction for use in transplantation, it has been demonstrated that cell therapy using hiPSC-derived NPCs ameliorates acute kidney injury (AKI) in mice. Disease modeling and drug discovery research using disease-specific hiPSCs has also been vigorously conducted for intractable kidney disorders, such as autosomal dominant polycystic kidney disease (ADPKD). In an attempt to address the complications associated with kidney diseases, hiPSC-derived erythropoietin (EPO)-producing cells were successfully generated to discover drugs and develop cell therapy for renal anemia. This review summarizes the current status and future perspectives of developmental biology of kidney and iPSC technology-based regenerative medicine for kidney diseases.
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Andrianova, Nadezda V., Marina I. Buyan, Ljubava D. Zorova, Irina B. Pevzner, Vasily A. Popkov, Valentina A. Babenko, Denis N. Silachev, Egor Y. Plotnikov et Dmitry B. Zorov. « Kidney Cells Regeneration : Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors ». International Journal of Molecular Sciences 20, no 24 (15 décembre 2019) : 6326. http://dx.doi.org/10.3390/ijms20246326.
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A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.
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Li, Ling, Rachel Black, Zhendong Ma, Qiwen Yang, Andrew Wang et Fangming Lin. « Use of mouse hematopoietic stem and progenitor cells to treat acute kidney injury ». American Journal of Physiology-Renal Physiology 302, no 1 (1 janvier 2012) : F9—F19. http://dx.doi.org/10.1152/ajprenal.00377.2011.
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New and effective treatment for acute kidney injury remains a challenge. Here, we induced mouse hematopoietic stem and progenitor cells (HSPC) to differentiate into cells that partially resemble a renal cell phenotype and tested their therapeutic potential. We sequentially treated HSPC with a combination of protein factors for 1 wk to generate a large number of cells that expressed renal developmentally regulated genes and protein. Cell fate conversion was associated with increased histone acetylation on promoters of renal-related genes. Further treatment of the cells with a histone deacetylase inhibitor improved the efficiency of cell conversion by sixfold. Treated cells formed tubular structures in three-dimensional cultures and were integrated into tubules of embryonic kidney organ cultures. When injected under the renal capsule, they integrated into renal tubules of postischemic kidneys and expressed the epithelial marker E-cadherin. No teratoma formation was detected 2 and 6 mo after cell injection, supporting the safety of using these cells. Furthermore, intravenous injection of the cells into mice with renal ischemic injury improved kidney function and morphology by increasing endogenous renal repair and decreasing tubular cell death. The cells produced biologically effective concentrations of renotrophic factors including VEGF, IGF-1, and HGF to stimulate epithelial proliferation and tubular repair. Our study indicates that hematopoietic stem and progenitor cells can be converted to a large number of renal-like cells within a short period for potential treatment of acute kidney injury.
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Kirpatovskiy, V. I., A. V. Sivkov, G. D. Efremov, S. I. Samoilova, E. V. Frolova et O. I. Apolikhin. « Experimental application of xenogenic fractionated proteomic secretome of stem and progenitor cells in acute ischemic kidney injury ». Experimental and Сlinical Urology 15, no 1 (30 mars 2022) : 10–19. http://dx.doi.org/10.29188/2222-8543-2022-15-1-10-19.
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Introduction. Currently, the possibilities of cell therapy using stem cells for the correction of functional disorders of organs, including kidneys, are being widely investigated. The main mechanism of action of stem cells is considered to be the activation of cellular regeneration and the inhibition of apoptosis by the products of their secretion (secretome), which makes it necessary to study the mechanisms of action of the stem cells secretome. Aim of study. To study the relationship of the nephroprotective effect of the drug, which is a protein-peptide secretom of embryonic brain cells (SESC), with its effect on the regeneration of kidney cells damaged by ischemia and the activity of their apoptosis. Material and methods. Experiments were carried out on 40 mongrel male rats weighing 280-320 g. Acute kidney injury of varying severity was caused by removal of the right kidney and ischemia of the remaining left kidney for 60 minutes or 90 minutes (20 rats per group). In each of these groups, 10 rats were injected daily subcutaneously with SESC at a dose of 0.1 ml/kg (10 injections), and the other 10 rats were not treated. After 3, 7 and 14 days, the ischemic kidney was removed and subjected to histological examination and histochemical determination of the expression of the proliferation marker Ki-67 and the anti-apoptotic protein Bcl-2 in the kidney structures. Results. In the treatment of SESC, up to 20% of hypertrophied renal glomeruli were detected already on the 3rd day in the absence of glomeruli with glomerulosclerosis, whereas in control experiments at this time hypertrophied glomeruli were not detected, and the proportion of glomeruli with signs of glomerulosclerosis was 5-10%. On the 7th and 14th days in both groups, the proportion of hypertrophied glomeruli increased, being compared in the group with 60-minute ischemia, but maintaining higher values in experiments with 90-minute ischemia and SESC therapy compared with the control. Glomeruli with glomerulosclerosis were significantly less frequently detected in the treatment of SESC, regardless of the severity of ischemic damage. At the same time, the expression of Bcl-2 in renal glomerular cells during SESC therapy decreased significantly to a lesser extent than in control experiments, confirming the relationship of inhibition of apoptosis during SESC therapy with inhibition of the development of sclerotic processes. A significant increase in the number of epithelial cells expressing the proliferation marker Ki-67 on the 3rd day, followed by a gradual decrease in their number, was detected in the renal tubules during SESC therapy, whereas in the control an increase in the number of labeled cells occurred only on the 7th and 14th days. With an increase in the severity of ischemic damage, the proliferation-stimulating effect of SESC was prolonged up to 14 days. The proliferative effect of SESC therapy was accompanied by a decrease in damage to the renal tubules, and the percentage of tubules with necrotic epithelium progressively decreased from 3-5% to 0-1% with an increase in the period after the start of therapy (7 and 14 days), indicating epithelial regeneration, while in the control their proportion remained at a higher level. Conclusion. Stimulation of cell proliferation and inhibition of apoptosis of damaged cells play an essential role in the nephroprotective effect of SESC, as in stem cells.
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Lazzeri, Elena, Maria Lucia Angelotti, Anna Julie Peired, Francesca Becherucci, Duccio Lombardi, Laura Lasagni et Paola Romagnani. « SP181PAX2+ PROGENITOR CELLS PLAY A KEY ROLE IN TUBULAR REGENERATION AFTER ACUTE KIDNEY INJURY ». Nephrology Dialysis Transplantation 31, suppl_1 (mai 2016) : i146. http://dx.doi.org/10.1093/ndt/gfw161.14.
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Schutgens, Frans, Maarten B. Rookmaaker, Francis Blokzijl, Ruben van Boxtel, Robert Vries, Edwin Cuppen, Marianne C. Verhaar et Hans Clevers. « Troy/TNFRSF19 marks epithelial progenitor cells during mouse kidney development that continue to contribute to turnover in adult kidney ». Proceedings of the National Academy of Sciences 114, no 52 (13 décembre 2017) : E11190—E11198. http://dx.doi.org/10.1073/pnas.1714145115.
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During kidney development, progressively committed progenitor cells give rise to the distinct segments of the nephron, the functional unit of the kidney. Similar segment-committed progenitor cells are thought to be involved in the homeostasis of adult kidney. However, markers for most segment-committed progenitor cells remain to be identified. Here, we evaluate Troy/TNFRSF19 as a segment-committed nephron progenitor cell marker. Troy is expressed in the ureteric bud during embryonic development. During postnatal nephrogenesis, Troy+ cells are present in the cortex and papilla and display an immature tubular phenotype. Tracing of Troy+ cells during nephrogenesis demonstrates that Troy+ cells clonally give rise to tubular structures that persist for up to 2 y after induction. Troy+ cells have a 40-fold higher capacity than Troy− cells to form organoids, which is considered a stem cell property in vitro. In the adult kidney, Troy+ cells are present in the papilla and these cells continue to contribute to collecting duct formation during homeostasis. The number of Troy-derived cells increases after folic acid-induced injury. Our data show that Troy marks a renal stem/progenitor cell population in the developing kidney that in adult kidney contributes to homeostasis, predominantly of the collecting duct, and regeneration.
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Ahmadi, Amin, Niloofar K. Rad, Vahid Ezzatizadeh et Reza Moghadasali. « Kidney Regeneration : Stem Cells as a New Trend ». Current Stem Cell Research & ; Therapy 15, no 3 (25 avril 2020) : 263–83. http://dx.doi.org/10.2174/1574888x15666191218094513.
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Renal disease is a major worldwide public health problem that affects one in ten people. Renal failure is caused by the irreversible loss of the structural and functional units of kidney (nephrons) due to acute and chronic injuries. In humans, new nephrons (nephrogenesis) are generated until the 36th week of gestation and no new nephron develops after birth. However, in rodents, nephrogenesis persists until the immediate postnatal period. The postnatal mammalian kidney can partly repair their nephrons. The kidney uses intrarenal and extra-renal cell sources for maintenance and repair. Currently, it is believed that dedifferentiation of surviving tubular epithelial cells and presence of resident stem cells have important roles in kidney repair. Many studies have shown that stem cells obtained from extra-renal sites such as the bone marrow, adipose and skeletal muscle tissues, in addition to umbilical cord and amniotic fluid, have potential therapeutic benefits. This review discusses the main mechanisms of renal regeneration by stem cells after a kidney injury.
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Gerges, Daniela, Zsofia Hevesi, Sophie H. Schmidt, Sebastian Kapps, Sahra Pajenda, Barbara Geist, Alice Schmidt, Ludwig Wagner et Wolfgang Winnicki. « Tubular epithelial progenitors are excreted in urine during recovery from severe acute kidney injury and are able to expand and differentiate in vitro ». PeerJ 10 (20 octobre 2022) : e14110. http://dx.doi.org/10.7717/peerj.14110.
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Background Acute kidney injury (AKI) is a serious condition associated with chronic kidney disease, dialysis requirement and a high risk of death. However, there are specialized repair mechanisms for the nephron, and migrated committed progenitor cells are the key players. Previous work has described a positive association between renal recovery and the excretion of tubular progenitor cells in the urine of kidney transplant recipients. The aim of this work was to describe such structures in non-transplanted AKI patients and to focus on their differentiation. Methods Morning urine was obtained from four patients with AKI stage 3 and need for RRT on a consecutive basis. Urine sediment gene expression was performed to assess which part of the tubular or glomerular segment was affected by injury, along with measurement of neprilysin. Urine output and sediment morphology were monitored, viable hyperplastic tubular epithelial clusters were isolated and characterized by antibody or cultured in vitro. These cells were monitored by phase contrast microscopy, gene, and protein expression over 9 days by qPCR and confocal immunofluorescence. Furthermore, UMOD secretion into the supernatant was quantitatively measured. Results Urinary neprilysin decreased rapidly with increasing urinary volume in ischemic, toxic, nephritic, and infection-associated AKI, whereas the decrease in sCr required at least 2 weeks. While urine output increased, dead cells were present in the sediment along with debris followed by hyperplastic agglomerates. Monitoring of urine sediment for tubular cell-specific gene transcript levels NPHS2 (podocyte), AQP1 and AQP6 (proximal tubule), and SLC12A1 (distal tubule) by qPCR revealed different components depending on the cause of AKI. Confocal immunofluorescence staining confirmed the presence of intact nephron-specific epithelial cells, some of which appeared in clusters expressing AQP1 and PAX8 and were 53% positive for the stem cell marker PROM1. Isolated tubule epithelial progenitor cells were grown in vitro, expanded, and reached confluence within 5–7 days, while the expression of AQP1 and UMOD increased, whereas PROM1 and Ki67 decreased. This was accompanied by a change in cell morphology from a disproportionately high nuclear/cytoplasmic ratio at day 2–7 with mitotic figures. In contrast, an apoptotic morphology of approximately 30% was found at day 9 with the appearance of multinucleated cells that were associable with different regions of the nephron tubule by marker proteins. At the same time, UMOD was detected in the culture supernatant. Conclusion During renal recovery, a high replicatory potential of tubular epithelial progenitor cells is found in urine. In vitro expansion and gene expression show differentiation into tubular cells with marker proteins specific for different nephron regions.
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Miya, Masaaki, Akito Maeshima, Keiichiro Mishima, Noriyuki Sakurai, Hidekazu Ikeuchi, Takashi Kuroiwa, Keiju Hiromura et Yoshihisa Nojima. « Age-related decline in label-retaining tubular cells : implication for reduced regenerative capacity after injury in the aging kidney ». American Journal of Physiology-Renal Physiology 302, no 6 (15 mars 2012) : F694—F702. http://dx.doi.org/10.1152/ajprenal.00249.2011.
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Recovery after acute kidney injury is impaired in the elderly, but the precise mechanism for such age-related incompetence remains unclear. By in vivo bromodeoxyuridine (BrdU) labeling, renal progenitor cells (label-retaining cells; LRCs) were identified in tubules of normal rat kidney and were shown to be the origin of proliferating cells after injury. In the present study, the involvement of LRCs in the age-related decline of tubular recovery after injury was examined. After 1 wk of BrdU labeling followed by a 2-wk chase period, ischemia-reperfusion injury was induced in 7-wk-, 7-mo-, and 12-mo-old rats. Age-related decreases in DNA synthesis and cell proliferation in renal tubules after injury were found. The number of LRCs also significantly declined with age. At 24 h after reperfusion, the number of LRCs significantly increased in all ages of rats tested. There was no significant difference in the ratio of LRC division among rats of different ages. The area of the rat endothelial cell antigen (RECA)-1-positive capillary network declined with age. When renal tubules isolated from rats treated with BrdU label were cocultured with human umbilical vein endothelial cells (HUVEC), the number of LRCs significantly increased compared with tubules cultured without HUVEC. These data suggest that the reduced capacity of tubular regeneration in the aging kidney is partly explained by the shortage of LRC reserves. The size of the LRC pool might be regulated by the surrounding peritubular capillary network.
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Burgos-Silva, Marina, Cassiano Donizetti-Oliveira, Marco Antonio Cenedeze, Denise Maria Avancini Costa Malheiros, Marlene Antônia dos Reis, Álvaro Pacheco-Silva, Patricia Semedo et Niels Olsen Saraiva Câmara. « Bone marrow mesenchymal stem cells protect against folic acid- induced acute kidney injury ». Brazilian Journal of Transplantation 15, no 2 (1 mars 2012) : 1661–65. http://dx.doi.org/10.53855/bjt.v15i2.178.
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Acute kidney injury constitutes a syndrome responsible by a major percentage of acute kidney failures and it continues being associated to high mortality rates. Induced mainly by ischemia-reperfusion injury and nephrotoxic drugs, this condition is marked by a decrease in organ function and histopathological pattern of acute tubular necrosis. In search of more efficient therapies, a great deal of attention has been given to the therapeutic use of stem cells to treat kidney injuries. Bone marrow stem cells in particular have received a great attention due to its immunomodulatory properties, and its therapeutic mechanisms are intensely being studied in the literature. Purpose: In view of recent findings, the aim of our research was to get a better understanding on the potential role of bone marrow mesenchymal stem cells in a murine model of acute nephotoxicity induced by folic acid. Methods: C57Bl/6j mice (8 weeks) were submitted to acute kidney injury by folic acid (200mg/kg) administered intraperitoneally. After 24 hours, mice received mesenchymal stem cells (5.105 cells per animal) through retro-orbital intravenous injection. Mice were sacrificed after 24 hours and blood and kidneys were harvested for analysis. Results: Stem cell treatment conferred functional improvement seen through lower creatinine and urea serum levels in 8 week old C57Bl/6j mice in comparison to mice treated only with folic acid (200mg/kg body weight). This amelioration are also correlated to down regulation of kidney pro-inflammatory cytokine mRNA levels as TNF-a, IL-6 and IL-1b in stem cell treated mice. In addition, treated mice demonstrated higher levels of immunostaining for proliferating cell nuclear antigen and a tendency towards a higher Bcl-2/Bax mRNA ratio, indicating higher tissue regeneration and protection against injury-induced apoptosis. Conclusion: These results indicate bone marrow stem cells as an efficient tool in nephrotoxic kidney injury treatment.
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Lemos, Dario R., Graham Marsh, Angela Huang, Gabriela Campanholle, Takahide Aburatani, Lan Dang, Ivan Gomez et al. « Maintenance of vascular integrity by pericytes is essential for normal kidney function ». American Journal of Physiology-Renal Physiology 311, no 6 (1 décembre 2016) : F1230—F1242. http://dx.doi.org/10.1152/ajprenal.00030.2016.
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Pericytes are tissue-resident mesenchymal progenitor cells anatomically associated with the vasculature that have been shown to participate in tissue regeneration. Here, we tested the hypothesis that kidney pericytes, derived from FoxD1+ mesodermal progenitors during embryogenesis, are necessary for postnatal kidney homeostasis. Diphtheria toxin delivery to FoxD1Cre::RsDTR transgenic mice resulted in selective ablation of >90% of kidney pericytes but not other cell lineages. Abrupt increases in plasma creatinine, blood urea nitrogen, and albuminuria within 96 h indicated acute kidney injury in pericyte-ablated mice. Loss of pericytes led to a rapid accumulation of neutral lipid vacuoles, swollen mitochondria, and apoptosis in tubular epithelial cells. Pericyte ablation led to endothelial cell swelling, reduced expression of vascular homeostasis markers, and peritubular capillary loss. Despite the observed injury, no signs of the acute inflammatory response were observed. Pathway enrichment analysis of genes expressed in kidney pericytes in vivo identified basement membrane proteins, angiogenic factors, and factors regulating vascular tone as major regulators of vascular function. Using novel microphysiological devices, we recapitulated human kidney peritubular capillaries coated with pericytes and showed that pericytes regulate permeability, basement membrane deposition, and microvascular tone. These findings suggest that through the active support of the microvasculature, pericytes are essential to adult kidney homeostasis.
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Cicero, Viviana Lo, Tiziana Montemurro, Marina Morigi, Daniela Corna, Lucilla Lecchi, Rosaria Giordano, Paolo Rebulla, Giuseppe Remuzzi et Lorenza Lazzari. « Cord Blood Mesenchymal Stem Cells for Acute Renal Failure Repair. » Blood 108, no 11 (16 novembre 2006) : 282. http://dx.doi.org/10.1182/blood.v108.11.282.282.
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Abstract Introduction: Human cord blood (CB) represents an interesting source of mesenchymal stem cells (MSCs) with different cell “competence” and feasible clinical applications. Up to now patients affected by acute renal failure (ARF) are treated by unsuccessful pharmacological therapies and it is an interesting possibility that CB MSCs or other potential progenitor cell subpopulations could be used for therapeutic purpose in renal repair. Aim of this study was to isolate and culture MSCs from full-term UCB and to test their ability to promote renal repair when transplanted into NOD-SCID mice with acute renal failure. Methods: MSCs were isolated with a lineage-depletion negative immuno-selection procedure (Rosette Sep, StemCell Technologies, Vancouver, Canada) from buffy coat of CB (n=17) without lysis of red blood cells. Cell suspension was seeded at 1×106 cells/cm2, in 35mm/tissue culture dish in the presence of αMEM, 20 % FBS, 2mM L-Glutamine and Penicillin/Streptomycin. Immunophenotype was evaluated by flow cytometric analysis while the differentiation assays were performed towards adipogenic, osteogenic and chondrogenic lineages in order to confirm their mesenchymal features. To induce acute renal failure, NOD-SCID mice (n=10) were injected with cisplatin (12.7 mg/KG s.c.). This drug is associated with renal function deterioration, measured as serum blood urea nitrogen (BUN), peaking at day 4–5. After one day the mice received i.v. saline or 5×105 CB MSCs. Renal function and histology were evaluated. Results: The success rate of isolating MSCs from CB units was 17.6%. Flow cytometric analysis showed that MSCs were positive for CD44 (69%), CD105 (26%), CD90 (99%), HLA class I (80%) and negative for CD31, CD45, CD34, HLA class II. Moreover, within the CB MSCs we identified a subpopulation (37.5%) characterized by CD146+/34−/45− and consistent with perivascular/pericyte-like cells. Moreover we demonstrated and confirmed that CB MSCs were capable to differentiate in osteogenic and condrogenic but not adipogenic lineages, as recently shown also by other groups. In vitro differentiation towards epithelial lineage is in progress. In vivo results showed that CB MSCs significantly protected cisplatin-treated mice from renal function impairment at day 4 (BUN: cisplatin+saline 115±5 vs cisplatin+CB MSCs 64±13 mg/dl, p<0.01). Kidneys of mice at 4 days after cisplatin injection were examined histologically and assigned scores (0 to 3) for tubular cell degeneration changes, hyaline casts and cell lysis. Mice receiving CB MSCs exhibited lower degree of tubular injury compared to mice given saline (average score: CB MSCs 0.5, range from 0.3 to 1 vs cisplatin + saline, 1, range 0.7 to 1.3, p<0.047). Conclusion: These preliminary results indicate that human CB MSCs exhibit reparative potential in acute renal failure. More evidences demonstrating the plasticity of CB stem cells will provide an exciting opportunity to explore the use of this stem cell source in regenerative medicine for patients with renal disease.
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Birtwistle, Lucy, Xin-Ming Chen et Carol Pollock. « Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury ». International Journal of Molecular Sciences 22, no 12 (20 juin 2021) : 6596. http://dx.doi.org/10.3390/ijms22126596.
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Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.
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Simone, Simona, Carmela Cosola, Antonia Loverre, Marica Cariello, Fabio Sallustio, Federica Rascio, Loreto Gesualdo, Francesco Paolo Schena, Giuseppe Grandaliano et Giovanni Pertosa. « BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation ». American Journal of Physiology-Renal Physiology 303, no 1 (1 juillet 2012) : F23—F34. http://dx.doi.org/10.1152/ajprenal.00328.2011.
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Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced α-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, α-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H2O2) induced α-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage.
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Ohtake, Takayasu, Shuzo Kobayashi, Shimon Slavin, Yasuhiro Mochida, Kunihiro Ishioka, Hidekazu Moriya, Sumi Hidaka et al. « Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice ». Cell Transplantation 27, no 3 (mars 2018) : 520–30. http://dx.doi.org/10.1177/0963689717753186.
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Acute kidney injury (AKI) is a major clinical problem that still has no established treatment. We investigated the efficacy of cultured human peripheral blood mononuclear cells (PBMNCs) for AKI. Ischemia/reperfusion injury (IRI) was used to induce AKI in male nonobese diabetic (NOD/severe combined immunodeficiency) mice aged 7 to 8 wk. PBMNCs were isolated from healthy volunteers and were subjected to quality and quantity controlled (QQc) culture for 7 d in medium containing stem cell factor, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin 6. IRI-induced mice were divided into 3 groups and administered (1) 1 × 106 PBMNCs after QQc culture (QQc PBMNCs group), (2) 1 × 106 PBMNCs without QQc culture (non-QQc PBMNCs group), or (3) vehicle without PBMNCs (IRI control group). PBMNCs were injected via the tail vein 24 h after induction of IRI, followed by assessment of renal function, histological changes, and homing of injected cells. Blood urea nitrogen and serum creatinine (Cr) 72 h after induction of IRI in the QQc PBMNCs group dramatically improved compared with those in the IRI control and the non-QQc PBMNCs groups, accompanied by the improvement of tubular damages. Interstitial fibrosis 14 d after induction of IRI was also significantly improved in the QQc PBMNCs group compared with the other groups. The renoprotective effect noted in the QQc PBMNCs group was accompanied by reduction of peritubular capillary loss. The change of PBMNCs’ population (increase of CD34+ cells, CD133+ cells, and CD206+ cells) and increased endothelial progenitor cell colony-forming potential by QQc culture might be one of the beneficial mechanisms for restoring AKI. In conclusion, an injection of human QQc PBMNCs 24 h after induction of IRI dramatically improved AKI in mice.
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Picerno, Angela, Francesca Giannuzzi, Claudia Curci, Mariagiovanna DI Chiano, Giuseppe De Palma, Rossana Franzin, Simona Simone et al. « FC023 : Human Adult Renal Progenitor Cells Secrete in the Kidney Very High Levels of the Anti-Ageing Protein Klotho Sustained by the Long No-Coding RNA Hotair ». Nephrology Dialysis Transplantation 37, Supplement_3 (mai 2022). http://dx.doi.org/10.1093/ndt/gfac099.002.
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Abstract BACKGROUND AND AIMS The complex system of human adult renal stem/progenitor cells (ARPCs) and their crucial role in the renewal of epithelial renal cells and regenerative processes in the adult kidneys have been recently discovered. In the human kidney, CD133+/CD24+ ARPCs are present within different segments of the nephron as a population with epithelial expansion, self-renewal and differentiation capabilities. Understanding the factors that regulate the ARPCs behaviour is fundamental to completely take advantage of their potential and to develop treatments for renal injury. Recent studies showed that long no-coding RNA (lncRNAs) are essential to establish developmental patterning and maintain the stem cell pluripotency network, further underscoring their important role in stem cell biology/technology and cellular reprogramming. lncRNAs can be dysregulated in different types of diseases and can also modulate the cellular senescence processes. For the first time, we studied their function in ARPCs showing that they express high levels of a particular lncRNA, HOTAIR, influencing cell senescence. METHOD Whole-genome lncRNA expression was performed by Agilent microarray. lncRNA expression was validated by real-time PCR. CRISPR/Cas9 system has been used to knock-down HOTAIR lncRNA. SA-β-Gal experiments were used to evaluate cellular senescence in normal ARPCs and ARPCs knock-out for HOTAIR. By ELISA, it was evaluated the expression of secreted anti-ageing protein Klotho. Fluorescence-activated cell sorting (FACS) was applied to measure CD133 and protein p15 expression in normal and transfected cells. Chromatin immunoprecipitation assay (ChIP) was used to evaluate H3K27me3 in the promoter of p15. RESULTS We studied the lncRNA profile of renal proximal tubular cells (RPTEC) and tubular ARPCs. We found 611 lncRNAs specifically expressed in ARPCs compared with RPTECs (Fold Change > 2; FDR < 0.05). Among the most significantly modulated lncRNAs, we demonstrated that the lncRNA HOX Transcript Antisense RNA (HOTAIR) is highly expressed in ARPCs (Fold change = 15; P < 0.001). To study the functions related to the ARPCs properties, knock-out cell lines for HOTAIR were created by the CRISPR/Cas9 technique. The silenced lines for HOTAIR immediately assumed a senescent phenotype confirmed by the beta-galactosidase assay and decreased proliferation (proliferation rate of ˂60%, P < 0.001). Moreover, we found that the constitutional, functional and inverse-senescence marker CD133+ was downregulated in knock-out cells (Fold change = 15; P < 0.01). We then studied the secreted levels of the anti-ageing protein α-Klotho which is essential to the maintenance of normal renal function and has potential clinical applications in the diagnosis of acute renal failure (AKI) and chronic kidney disease (CKD). We discovered that ARPCs produce α-Klotho at much higher levels compared to RPTEC, at a mean concentration of 200 pg/mL versus 33 pg/mL (Fold increase = 6.6; P < 0.001). Interestingly, following the HOTAIR knock-out, the levels of α-Klotho secreted by the ARPCs dropped sharply, with a 4-fold decrease (P < .001). In addition, we found that HOTAIR was responsible for the ARPC self-renewal through the epigenetic induction of the cell cycle inhibitor p15 through the trimethylation of histone H3K27 associated with the promoter region of p15. In ARPCs knock-out for HOTAIR p15 increased significantly (Fold increase = 3; P < 0.005) and the H3K27me3 in the promoter of p15 was less enriched (Fold decrease = 1.5; P < 0.05), leading to the increase of the cell cycle inhibitor and cell senescence. CONCLUSION These data demonstrated that HOTAIR regulates the self-renewal capacity of ARPCs and prevents them from becoming senescent in the short term. Moreover, HOTAIR influences ARPC ability to secrete high levels of α-Klotho, and those renal progenitors, through α-Klotho secretion, are able to influence its levels in surrounding tissues and to modulate, therefore, kidney ageing.
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Curci, Claudia, Fabio Sallustio, Angela Picerno, Alessandra Stasi, Maria Teresa Cimarrusti, Paola Pontrelli, Giuseppe Castellano, Simona Simone, Pertosa Giovanni et Loreto Gesualdo. « P0021LONG NON-CODING RNAS HOTAIR AND LINC00511 CAN EXPLAIN HUMAN RENAL STEM/PROGENITOR CELLS CAPACITY TO REPAIR DAMAGE INDUCED BY CISPLATIN ». Nephrology Dialysis Transplantation 35, Supplement_3 (1 juin 2020). http://dx.doi.org/10.1093/ndt/gfaa142.p0021.
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Abstract Background and Aims The recent discovery of a complex system of human Adult renal stem/progenitor cells (ARPCs) dedicated to the renewal of epithelial renal cells has allowed scientists to better understand how the regenerative process can occur in the adult kidney. ARPCs have a great potential in view of developing future treatments for both acute and chronic renal injury. However, to completely take advantage of their capability it is essential to study the factors regulating the stem cell behavior. Recently, long noncoding RNAs (lncRNAs) have been recognized as a crucial class of gene expression regulators. lncRNAs have several distinguishing characteristics that provide particular regulatory functions, including cell- and tissue-specific expression and the ability to transduce higher-order spatial information. Several lncRNAs modulate some somatic stem cell renewal or differentiation, while others promote a differentiation program. Their functions are often helped by proteic co-factor that convey the ability to activate or repress gene expression or to post-transcriptionally regulate other RNAs. Furthermore, numerous lncRNAs have been shown to act as competing endogenous RNAs, where the lncRNAs are proposed to bind to and compete miRNAs away from cognate mRNA targets. The aim of the study was to evaluate the basal expression profile of lncRNA expressed specifically in ARPCs. Method lncRNA expression profile was obtained from ARPCs and renal proximal tubular cells (RPTECs) alone or following cisplatin damage induction. We used Agilent SurePrint G3 Human Gene Expression Microarrays providing comprehensive coverage of genes and transcripts using the latest annotation databases. Genespring and R software were used for the analysis. lncRNA expression was validated by Real-time PCR. CrispR/Cas9 system has been used to knock-down specific lncRNA. Results We compared lncRNA expression between ARPCs and RPTECs: 45 lncRNA were differently modulated in ARPCs vs RPTECs (Fold change 1.5; FDR <0.05). In particular, we found 13 lncRNA upregulated and 32 lncRNA downregulated. Classification analysis showed that most of lncRNA modulated in ARPCs interfere with WNT signaling pathway, immune cell activation, and G-protein signaling pathway. Moreover, the overrepresentation test showed their involvement in calcium-mediated signaling, cell cycle and protein glycosylation processes (p<0.005). Among most significantly modulated lincRNAs we found HOTAIR and CCND2-AS1 that were upregulated in ARPCs compared to RPTECs. When we knocked-down the HOTAIR lncRNA ARPCs were not able to normally proliferate in cell culture. However, following cisplatin damage induced in RPTECs, ARPCs upregulated the LINC00511 and the miR210-HG. LINC00511 binds histone methyltransferase enhancer of zeste homolog 2 (EZH2, the catalytic subunit of the polycomb repressive complex 2 - PRC2), a highly conserved protein complex that regulates gene expression by methylating lysine 27 on histone H3. It acts as a modular scaffold of EZH2/PRC2 complexes, coordinates their localization, and specifies the histone modification pattern on the target genes, including p57. LINC00511 can affect cell proliferation, invasiveness, and apoptosis. Conclusion ARPCs express specific lncRNAs that could explain some of the ARPC stemness properties and their capacity to repair damage induced by cisplatin. Our findings suggest that lncRNA may represent a novel therapeutic target in acute and chronic renal injury.
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Stamellou, Eleni, Katja Leuchtle et Marcus J. Moeller. « Regenerating tubular epithelial cells of the kidney ». Nephrology Dialysis Transplantation, 15 juillet 2020. http://dx.doi.org/10.1093/ndt/gfaa103.
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Abstract Acute tubular injury accounts for the most common intrinsic cause for acute kidney injury. Normally, the tubular epithelium is mitotically quiescent. However, upon injury, it can show a brisk capacity to regenerate and repair. The scattered tubular cell (STC) phenotype was discovered as a uniform reaction of tubule cells triggered by injury. The STC phenotype is characterized by a unique protein expression profile, increased robustness during tubular damage and increased proliferation. Nevertheless, the exact origin and identity of these cells have been unveiled only in part. Here, we discuss the classical concept of renal regeneration. According to this model, surviving cells dedifferentiate and divide to replace neighbouring lost tubular cells. However, this view has been challenged by the concept of a pre-existing and fixed population of intratubular progenitor cells. This review presents a significant body of previous work and animal studies using lineage-tracing methods that have investigated the regeneration of tubular cells. We review the experimental findings and discuss whether they support the progenitor hypothesis or the classical concept of renal tubular regeneration. We come to the conclusion that any proximal tubular cell may differentiate into the regenerative STC phenotype upon injury thus contributing to regeneration, and these cells differentiate back into tubular cells once regeneration is finished.
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Hansson, J., A. E. Ericsson, H. Axelson et M. E. Johansson. « Species diversity regarding the presence of proximal tubular progenitor cells of the kidney ». European Journal of Histochemistry 60, no 1 (5 février 2016). http://dx.doi.org/10.4081/ejh.2016.2567.
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<p>The cellular source for tubular regeneration following kidney injury is a matter of dispute, with reports suggesting a stem or progenitor cells as the regeneration source while linage tracing studies in mice seemingly favor the classical theory, where regeneration is performed by randomly surviving cells. We, and others have previously described a scattered cell population localized to the tubules of human kidney, which increases in number following injury. Here we have characterized the species distribution of these proximal tubular progenitor cells (PTPCs) in kidney tissue from chimpanzee, pig, rat and mouse using a set of human PTPC markers. We detected PTPCs in chimpanzee and pig kidneys, but not in mouse tissue. Also, subjecting mice to the unilateral urethral obstruction model, caused clear signs of tubular injury, but failed to induce the PTPC phenotype in renal tubules.</p>
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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, no 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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Mamillapalli, Ramanaiah, SiHyun Cho, Levent Mutlu et Hugh S. Taylor. « Therapeutic role of uterine-derived stem cells in acute kidney injury ». Stem Cell Research & ; Therapy 13, no 1 (12 mars 2022). http://dx.doi.org/10.1186/s13287-022-02789-0.
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Abstract Background Acute kidney injury (AKI) causes abrupt deterioration in kidney function that disrupts metabolic, electrolyte and fluid homeostasis. Although the prevalence of AKI is steadily increasing, no definitive treatment options are available, leading to severe morbidity and mortality. We evaluated the role of uterine-derived multipotent stem cells in kidney regeneration after ischemic AKI. Methods Female C57BL/6J mice were hysterectomized and subsequently subject to AKI by either unilateral or bilateral renal ischemia–reperfusion injury. Uterine-derived cells (UDCs), containing a population of uterine stem cells, were isolated from the uteri of female transgenic DsRed mice and injected intravenously to AKI mice. Engraftment of DsRed cells was analyzed by flow cytometry while serum creatinine levels were determined colorimetrically. Expression of UDC markers and cytokine markers were analyzed by immunohistochemical and qRT-PCR methods, respectively. The Kaplan–Meier method was used to analyze survival time while unpaired t test with Welch’s correction used for data analysis between two groups. Results Mice with an intact uterus, and hence an endogenous source of UDCs, had a higher survival rate after bilateral ischemic AKI compared to hysterectomized mice. Mice treated with infusion of exogenous UDCs after hysterectomy/AKI had lower serum creatinine levels and higher survival rates compared to controls that did not receive UDCs. Engraftment of labeled UDCs was significantly higher in kidneys of bilateral ischemic AKI mice compared to those that underwent a sham surgery. When unilateral ischemic AKI was induced, higher numbers of UDCs were found in the injured than non-injured kidney. Immunofluorescence staining demonstrated double-positive DsRed/Lotus tetragonolobus agglutinin (LTA) positive cells and DsRed/CD31 positive cells indicating contribution of UDCs in renal tubular and vascular regeneration. Expression of Cxcl12, Bmp2, Bmp4, and Ctnf in renal tissue was significantly higher in the UDCs injection group than the control group. Conclusions UDCs engrafted injured kidneys, contributed to proximal tubule and vascular regeneration, improved kidney function and increased survival in AKI mice. UDC administration is a promising new therapy for AKI. Endogenous uterine stem cells likely also preserve kidney function, suggesting a novel interaction between the uterus and kidney. We suggest that hysterectomy may have a detrimental effect on response to renal injury.
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Huang, Jianni, Hao Cao, Binbin Cui, Xiaoyan Ma, Ling Gao, Chao Yu, Fengchen Shen et al. « Mesenchymal Stem Cells-Derived Exosomes Ameliorate Ischemia/Reperfusion Induced Acute Kidney Injury in a Porcine Model ». Frontiers in Cell and Developmental Biology 10 (24 mai 2022). http://dx.doi.org/10.3389/fcell.2022.899869.
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Exosomes are membrane-enclosed vesicles secreted by cells, containing a variety of biologically active ingredients including proteins, nucleic acids and lipids. In this study, we investigated the therapeutic effects of the exosomes and underlying mechanisms in a miniature pig model of ischemia/reperfusion-induced acute kidney injury (I/R-AKI). The exosomes were extracted from cultured human umbilical cord derived mesenchymal stem cells (hUC-MSCs) and infused into a miniature pig model of I/R AKI. Our results showed that 120 min of unilateral ischemia followed by reperfusion and contralateral nephrectomy resulted in renal dysfunction, severe kidney damage, apoptosis and necroptosis. Intravenous infusion of one dose of exosomes collected from about 4 × 108 hUC-MSCs significantly improved renal function and reduced apoptosis and necroptosis. Administration of hUC-MSC exosomes also reduced the expression of some pro-inflammatory cytokines/chemokines, decreased infiltration of macrophages to the injured kidneys and suppressed the phosphorylation of nuclear factor-κB and signal transducer and activator of transcription 3, two transcriptional factors related to inflammatory regulation. Moreover, hUC-MSC exosomes could promote proliferation of renal tubular cells, angiogenesis and upregulation of Klotho and Bone Morphogenetic Protein 7, two renoprotective molecules and vascular endothelial growth factor A and its receptor. Collectively, our results suggest that injection of hUC-MSC exosomes could ameliorate I/R-AKI and accelerate renal tubular cell repair and regeneration, and that hUC-MSC exosomes may be used as a potential biological therapy for Acute kidney injury patients.
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Tsugawa-Shimizu, Yuri, Yuya Fujishima, Shunbun Kita, Satoshi Minami, Taka-aki Sakaue, Yuto Nakamura, Tomonori Okita et al. « Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin ». American Journal of Physiology-Endocrinology and Metabolism, 7 décembre 2020. http://dx.doi.org/10.1152/ajpendo.00393.2020.
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Adiponectin (APN) is a circulating protein specifically produced by adipocytes. Native APN specifically binds to T-cadherin, a glycosylphosphatidylinositol-anchored protein, mediating the exosome-stimulating effects of APN in endothelial, muscle, and mesenchymal stem cells. It was previously reported that APN has beneficial effects on kidney diseases, but the role of T-cadherin has not been clarified yet. Here, our immunofluorescence study indicated the existence of both T-cadherin and APN protein in pericytes, subsets of tissue-resident mesenchymal stem/progenitor cells positive for PDGFRβ, surrounding peritubular capillaries. In an acute renal ischemia-reperfusion (I/R) model, T-cadherin-KO mice, similar to APN-KO mice, exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability than wild-type mice. In addition, in response to I/R injury, the renal PDGFRβ-positive cell area increased in wild-type mice, but opposingly decreased both in Tcad-KO and APN-KO mice, suggesting severe pericyte loss. Mouse primary pericytes also expressed T-cadherin. APN promoted exosome secretion in a T-cadherin-dependent manner. Such exosome production from pericytes may play an important role in maintaining the capillary network and APN-mediated inhibition of renal tubular injury. In summary, our study suggested that APN protected the kidney in an acute renal injury model by binding to T-cadherin.
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Moonen, Lies, Elena Lazzeri, Anna Julie Peired, Carolina Conte, Patrick D'Haese, Paola Romagnani et Benjamin Vervaet. « MO337UNILATERAL NEPHRECTOMY OVERCOMES PROGRESSION TO CHRONIC KIDNEY DISEASE AFTER ACUTE INJURY IN MICE BY STIMULATING PROLIFERATION OF RENAL PROGENITOR CELLS ». Nephrology Dialysis Transplantation 36, Supplement_1 (1 mai 2021). http://dx.doi.org/10.1093/ndt/gfab084.0010.
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Abstract Background and Aims Acute kidney injury (AKI) is a global health concern with an incidence of 13.3 million patients per year, and increasing. AKI is recognized as an important risk factor for the development of chronic kidney disease (CKD). A crucial aspect for successful renal recovery after AKI is an efficient proliferative response of surviving tubular epithelial cells (TECs). Recently, we established a murine model in which the functional and histological recovery of a single kidney, injured by ischemia, is enhanced by removal of the unharmed contralateral kidney; a phenomenon termed nephrectomy-induced recovery. The renal epithelial reparative response in this unique physiological model has not been investigated, yet can provide new insights in unlocking the inherent regenerative potential of the renal epithelium. Method AKI was induced in R26RtdTomato and PAX2/Confetti mice by left unilateral ischemia/reperfusion (UIRI) for 21 min at 34°C, after which either right nephrectomy (Nx) or no Nx was performed 3 days later. Mice were euthanized 6 weeks and 28 days after UIRI, respectively. At week 6, kidneys were weighted and renal function was assessed by serum creatinine. At 28 days, renal tissue of Pax2/Confetti mice was collected to perform renal progenitor cell lineage tracing experiments by immunofluorescence and confocal microscopy. Results When nephrectomy was performed after UIRI, left kidney-to-body weight ratio did not change significantly over time, whereas, when no nephrectomy was performed, left kidney-to-body weight ratio gradually declined from 7,84 ± 0,48 mg/dl at day 3 till 3,26 ± 0,51 mg/dl at week 6, indicating severe atrophy in the injured left kidney. This loss of renal mass was associated with a significant increase in serum creatinine (1,76 ± 0,13 mg/dl) as compared to control (0,21 ± 0,12 mg/dl), whereas with nephrectomy, renal function fully restored. Clonal analysis in PAX2/Confetti mice revealed that nephrectomy after UIRI led to a significant increase in proliferating (i.e. clonogenic) Pax2+ progenitor cells, resulting in more multicellular clones as compared to un-nephrectomized controls. Conclusion Nephrectomy after UIRI overcomes chronic loss of renal mass and function within the investigated 6-week time frame. This study is the first to demonstrate that nephrectomy stimulates clonal expansion of renal progenitor cells in an injured kidney, beyond that observed for spontaneous repair after UIRI. Insight in the signaling mechanisms may reveal new therapeutic approaches to incite the inherent renal regeneration potential.
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Peired, Anna Julie, Marco Allinovi, Giulia Antonelli, Maria Lucia Angelotti, Francesco Guzzi et Paola Romagnani. « MO060ACUTE KIDNEY INJURY PROMOTES DEVELOPMENT OF A PAPILLARY RENAL CELL ADENOMA-CARCINOMA SEQUENCE FROM RENAL PROGENITORS ». Nephrology Dialysis Transplantation 35, Supplement_3 (1 juin 2020). http://dx.doi.org/10.1093/ndt/gfaa140.mo060.
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Abstract Background and Aims Renal cell carcinoma (RCC) accounts for 2% of all cancers, with about 190,000 new cases per year worldwide. Risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. Acute tissue injury (AKI) causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. We proposed to verify whether AKI plays a role in RCC development, and to identify the cellular origin of RCC. Method We used the following techniques: 1. observational, retrospective clinical trial to identify a possible association of AKI with RCC. 2. Experimental AKI induction in wild-type mice to study tumor development over 36 weeks. 3. Analysis of TCGA Research Network dataset on human papillary RCC (pRCC) molecular characterization, focusing on AKI-driven pathways. 4. Development of mouse models in which the intracellular domain of Notch 1 (NICD1), a molecule modulated during AKI, is expressed constitutively by all Pax8+ tubular epithelial cells (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. The mice were sacrificed at 36 weeks or 4 weeks after AKI. 5. Clonal analysis of tumoral lesions with Confetti reporter. 6. Examination of single cell RNA sequencing (RNAseq) data from pRCC patients. Results We observed that an AKI episode is a major risk factor for pRCC development and recurrence in patients. Wild-type mice subjected to AKI developed pRCC over time in an adenoma-carcinoma sequence, corroborating our human findings. Among AKI-related pathways, Notch1 overexpression in human pRCC associated with worse outcome, prompting us to generate Notch1-overexpressing mice. At 36 weeks o at 4 weeks following AKI, Pax8/NICD1 mice presented a significant decline of renal excretory function as well as type 2 pRCCs. Confetti lineage tracing showed that most of the pRCCs were monoclonal or biclonal, suggesting that they could originate from a local stem cell/progenitor population. Pax2/NICD1 mice presented type 2 pRCCs, and lineage tracing identified single Pax2+ tubular progenitors as the source of pRCCs. Single cell RNAseq analysis confirmed that the molecular signature of the pRCC cell of origin matched the one of human tubular progenitors. Conclusion This study expose the link between AKI and pRCC development in patients, with important clinical implications. In mice, AKI promotes long-term development of type 2 papillary tumors by activating the AKI-associated Notch1 pathway. Additionally, pRCC originates from clonal proliferation of renal progenitors in a classical adenoma-carcinoma sequence leading to invasive pRCC growth and metastatization in mice.
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Chen, Zhi, Xiang Ren, Ruimin Ren, Yonghong Wang et Jiwen Shang. « The combination of G-CSF and AMD3100 mobilizes bone marrow-derived stem cells to protect against cisplatin-induced acute kidney injury in mice ». Stem Cell Research & ; Therapy 12, no 1 (24 mars 2021). http://dx.doi.org/10.1186/s13287-021-02268-y.
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Abstract Background Several studies have confirmed that mobilizing bone marrow-derived stem cells (BMSCs) ameliorates renal function loss following cisplatin-induced acute kidney injury (AKI). The aim of this study was to explore whether the combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor (AMD3100) exerts beneficial effects on renal function recovery in a model of cisplatin-induced nephrotoxicity. Methods C57BL/6J mice received intraperitoneal injections of G-CSF (200 μg/kg/day) for 5 consecutive days. On the day of the last injection, the mice received a single subcutaneous dose of AMD3100 (5 mg/kg) 1 h before cisplatin 20 mg/kg injection. Ninety-six hours after cisplatin injection, the mice were euthanized, and blood and tissue samples were collected to assess renal function and tissue damage. Cell mobilization was assessed by flow cytometry (FCM). Results Mice pretreated with G-CSF/AMD3100 exhibited longer survival and lower serum creatinine and blood urea nitrogen (BUN) levels than mice treated with only G-CSF or saline. Combinatorial G-CSF/AMD3100 treatment attenuated tissue injury and cell death, enhanced cell regeneration, and mobilized a higher number of stem cells in the peripheral blood than G-CSF or saline treatment. Furthermore, the mRNA expression of proinflammatory factors was lower, whereas that of anti-inflammatory factors was higher, in the G-CSF/AMD3100 group than in the G-CSF or saline group (all P < 0.05). Conclusions These results suggest that combinatorial G-CSF/AMD3100 therapy mobilizes BMSCs to accelerate improvements in renal functions and prevent cisplatin-induced renal tubular injury. This combinatorial therapy may represent a new therapeutic option for the treatment of AKI and should be further investigated in the future.
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Yang, Yuanjun, Xiaodong Geng, Kun Chi, Chao Liu, Ran Liu, Xiangmei Chen, Quan Hong et Guangyan Cai. « Ultrasound enhances the therapeutic potential of mesenchymal stem cells wrapped in greater omentum for aristolochic acid nephropathy ». Stem Cell Research & ; Therapy 12, no 1 (3 mai 2021). http://dx.doi.org/10.1186/s13287-021-02243-7.
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Abstract Background Mesenchymal stem cells (MSCs) have been reported to promote regeneration in both subjects with acute kidney injury (AKI) and chronic kidney disease (CKD), but their efficacy remains limited, probably because most of the cells accumulate in the lungs, liver, and spleen after an intravenous infusion. Therefore, ultrasound-guided administration of MSCs represents a possible approach to solve this problem. The greater omentum is used to promote cell survival due to its rich vasculature. We hypothesized that ultrasound-guided administration of MSCs combined with greater omentum might be more curative than currently available approaches. Methods In this study, we established an aristolochic acid nephropathy (AAN) model by intraperitoneally administering aristolochic acid I sodium salt (AA-I) at a dose of 5 mg/kg body weight on alternate days for 4 weeks. Subsequently, a laparotomy was performed, and the left kidney from which the capsule had been removed was wrapped with the greater omentum. A dose of 2 × 107 MSCs was injected into the space between the greater omentum and the left kidney. Equal amounts of MSCs were administered under ultrasound guidance every second week for a total of 4 treatments. Mice were sacrificed 4 weeks after surgery. Serum creatinine and blood urea levels were measured to assess renal function. qPCR, Western blot, and histological analyses were conducted to further investigate the therapeutic mechanism of MSCs. Results Ultrasound-guided injection of MSCs into the greater omentum that surrounds the kidney enriched cells in the kidney region for up to 5 days. Renal function tests indicated that MSCs improved renal function to a great extent, as reflected by decreased blood urea nitrogen and serum creatinine levels. In addition, histological analyses showed that MSCs noticeably attenuated kidney injury, as evidenced by the amelioration of tubular necrosis and peritubular interstitial fibrosis. Mitigation of renal interstitial fibrosis was further confirmed by immunohistochemistry, qPCR, and western blotting after MSC treatment. Moreover, immunofluorescence staining revealed that MSCs alleviated inflammatory responses by increasing the counts of CD206+ cells and decreasing the counts of CD68+ cells. MSC migration was initiated in response to AA-I-treated renal epithelial cells in an in vitro migration assay. Conclusions These findings suggested that administration of MSCs into the cavity formed by the injured kidney and the greater omentum under ultrasound guidance improved renal function, attenuated kidney injury, and mitigated renal interstitial fibrosis and inflammatory responses. Thus, this approach might be a safe and effective therapy for CKD.
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FRANZIN, ROSSANA, Fabio Sallustio, Claudia Curci, Simona Simone, Angela Picerno, Giuseppe Depalma, Giuseppe Castellano, Anna Gallone, Giovanni Battista Pertosa et Loreto Gesualdo. « P0517RENAL STEM CELLS (ARPCS) AS A NEPHROPROTECTIVE APPROACH DURING CISPLATIN-INDUCED ACUTE KIDNEY INJURY : A DEFENSE MECHANISM BY EXTRACELLULAR VESICLES CARRYING THE CYP1B1 GENE ». Nephrology Dialysis Transplantation 35, Supplement_3 (1 juin 2020). http://dx.doi.org/10.1093/ndt/gfaa143.p0517.
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Abstract Background and Aims Cisplatin, is a nonspecific cytotoxic agent that primarily interferes with cellular DNA replication and the cell cycle, nevertheless it lacks tumor selectivity and acts also in normal cells. The most serious adverse reaction of cisplatin is Acute Kidney Injury (AKI), limiting its use and efficacy in chemotherapy. Cisplatin nephrotoxicity is observed in more than 30% of older patients, however the mechanism of nephrotoxicity remains unclear and specific preventive measures are not available. Today, there is an urgent need for specific nephroprotective strategies to be used during cisplatin chemotherapy. Recently, we found that tubular stem/progenitor cells (tARPC) are able to protect the tubular epithelial (RPTEC) from cisplatin induced injury, preserving their proliferation and inhibiting apoptosis. The aim of this study was to identify the molecular mechanisms involved in tARPC-mediated resistance to cisplatin. Method Co-cultures of RPTEC cells and tARPCs were exposed to cisplatin (2.5 µM) for 6 h and then kept in culture for 96 h. Gene expression profile was obtained from tARPCs and RPTECs by Agilent SurePrint G3 Human Gene Expression Microarrays. Genespring and R software were used for the analysis. Gene expression data were validated by Real-time PCR. Extracellular vesicles were isolated from cell culture supernatant by miRCURY Exosome Cell/Urine/CSF Kit (Qiagen) and RNA contained in extracellular vesicles was purified, analyzed in quality by Bioanalyzer (RNA nano) and evaluated by qPCR. The BrdU assay and caspase 3 were used to measure proliferation and apoptosis levels. Immunohistochemical expression of activated caspase-3 was used as a marker of apoptosis in RPTECs. Results By a whole-genome gene expression analysis, we found 107 genes specifically modulated by RPTECs in response to cisplatin and, among these, 30 genes induced by ARPCs following the cisplatin damage. In particular, we found a strong upregulation of the CYP1B1 gene (false discovery rate corrected p value <0.05; fold change=4,1). The qPCR confirmed the increase in CYP1B1 levels in the co-cultures with respect to the respective basal conditions (p <0.05). Interestingly, the CYP1B1 mRNA was also enveloped in Extracellular Vesicles released in the cell co-culture media by tARPC and RPTEC after cisplatin exposition. The CYP1B1 gene encodes a member of the cytochrome P450 superfamily of enzymes and the produced enzyme metabolizes procarcinogens, such as polycyclic aromatic hydrocarbons. CYP1B1 has been shown to be active within tumors and is also capable of metabolizing a structurally diverse range of anticancer drugs. It is responsible for the resistance to docetaxel, cisplatin, tamoxifen and nucleoside analogues. CYP1B1 is involved in the detoxification of the body by various exogenous toxic agents, including cisplatin. We found that CYP1B1 gene was expressed at low levels in RPTECs and in cisplatin-damaged RPTECs. Moreover, 96 h days after 2.5 μM exposure to cisplatin, RPTECs reduced the proliferation and underwent in apoptosis, as showed by caspase 3. However, in co-culture with ARPCs, ARPC cellular and extracellular vesicles CYP1B1 gene expression significantly increased, the apoptotic process was stopped and RPTECs increased their proliferation rate. These data support the hypothesis that ARPCs are sensor of cisplatin damaged-RPTEC and confers cisplatin resistance by transferring CYP1B1 gene in extracellular vesicles. Conclusion This is the first evidence of a cisplatin-induced overexpression of CYP1b1 in renal epithelial cells as a defense mechanism against cisplatin toxicity. This is consistent with our previous data showing that renal progenitors are resistant to cisplatin. The findings may have biological and clinical significance in terms of their implications in cellular communications and potential use of CYP1B1 as biomarkers for AKI induced by cisplatin or as protective agent.