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1
Srinivas, Ampati. "The Constantly Highly Expression of Limbal Stromal Cells Compared to the Bone Marrow Mesenchymal Stromal Cells, Adipose-Derived Mesenchymal Stromal Cells and Foreskin Fibroblasts." Stem Cells Research and Therapeutics International 1, no. 1 (April 16, 2019): 01–06. http://dx.doi.org/10.31579/2643-1912/005.
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Cilloni, Daniela, Carmelo Carlo-Stella, Franca Falzetti, Gabriella Sammarelli, Ester Regazzi, Simona Colla, Vittorio Rizzoli, Franco Aversa, Massimo F. Martelli, and Antonio Tabilio. "Limited engraftment capacity of bone marrow–derived mesenchymal cells following T-cell–depleted hematopoietic stem cell transplantation." Blood 96, no. 10 (November 15, 2000): 3637–43. http://dx.doi.org/10.1182/blood.v96.10.3637.h8003637_3637_3643.
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The engraftment capacity of bone marrow–derived mesenchymal cells was investigated in 41 patients who had received a sex-mismatched, T-cell–depleted allograft from human leukocyte antigen (HLA)–matched or –mismatched family donors. Polymerase chain reaction (PCR) analysis of the human androgen receptor (HUMARA) or the amelogenin genes was used to detect donor-derived mesenchymal cells. Only 14 marrow samples (34%) from 41 consenting patients generated a marrow stromal layer adequate for PCR analysis. Monocyte-macrophage contamination of marrow stromal layers was reduced below the levels of sensitivity of HUMARA and amelogenin assays (5% and 3%, respectively) by repeated trypsinizations and treatment with the leucyl-leucine (leu-leu) methyl ester. Patients who received allografts from 12 female donors were analyzed by means of the HUMARA assay, and in 5 of 12 cases a partial female origin of stromal cells was demonstrated. Two patients who received allografts from male donors were analyzed by amplifying the amelogenin gene, and in both cases a partial male origin of stromal cells was shown. Fluorescent in situ hybridization analysis using a Y probe confirmed the results of PCR analysis and demonstrated in 2 cases the existence of a mixed chimerism at the stromal cell level. There was no statistical difference detected between the dose of fibroblast progenitors (colony-forming unit–F [CFU-F]) infused to patients with donor- or host-derived stromal cells (1.18 ± 0.13 × 104/kg vs 1.19 ± 0.19 × 104/kg; P ≥ .97). In conclusion, marrow stromal progenitors reinfused in patients receiving a T-cell–depleted allograft have a limited capacity of reconstituting marrow mesenchymal cells.
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Borges, Fernanda T., Marcia Bastos Convento, and Nestor Schor. "Bone marrow-derived mesenchymal stromal cell: what next?" Stem Cells and Cloning: Advances and Applications Volume 11 (November 2018): 77–83. http://dx.doi.org/10.2147/sccaa.s147804.
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Cilloni, Daniela, Carmelo Carlo-Stella, Franca Falzetti, Gabriella Sammarelli, Ester Regazzi, Simona Colla, Vittorio Rizzoli, Franco Aversa, Massimo F. Martelli, and Antonio Tabilio. "Limited engraftment capacity of bone marrow–derived mesenchymal cells following T-cell–depleted hematopoietic stem cell transplantation." Blood 96, no. 10 (November 15, 2000): 3637–43. http://dx.doi.org/10.1182/blood.v96.10.3637.
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Abstract The engraftment capacity of bone marrow–derived mesenchymal cells was investigated in 41 patients who had received a sex-mismatched, T-cell–depleted allograft from human leukocyte antigen (HLA)–matched or –mismatched family donors. Polymerase chain reaction (PCR) analysis of the human androgen receptor (HUMARA) or the amelogenin genes was used to detect donor-derived mesenchymal cells. Only 14 marrow samples (34%) from 41 consenting patients generated a marrow stromal layer adequate for PCR analysis. Monocyte-macrophage contamination of marrow stromal layers was reduced below the levels of sensitivity of HUMARA and amelogenin assays (5% and 3%, respectively) by repeated trypsinizations and treatment with the leucyl-leucine (leu-leu) methyl ester. Patients who received allografts from 12 female donors were analyzed by means of the HUMARA assay, and in 5 of 12 cases a partial female origin of stromal cells was demonstrated. Two patients who received allografts from male donors were analyzed by amplifying the amelogenin gene, and in both cases a partial male origin of stromal cells was shown. Fluorescent in situ hybridization analysis using a Y probe confirmed the results of PCR analysis and demonstrated in 2 cases the existence of a mixed chimerism at the stromal cell level. There was no statistical difference detected between the dose of fibroblast progenitors (colony-forming unit–F [CFU-F]) infused to patients with donor- or host-derived stromal cells (1.18 ± 0.13 × 104/kg vs 1.19 ± 0.19 × 104/kg; P ≥ .97). In conclusion, marrow stromal progenitors reinfused in patients receiving a T-cell–depleted allograft have a limited capacity of reconstituting marrow mesenchymal cells.
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Reyes, Morayma, Sheng Li, Jessica Foraker, En Kimura, and Jeffrey S. Chamberlain. "Donor origin of multipotent adult progenitor cells in radiation chimeras." Blood 106, no. 10 (November 15, 2005): 3646–49. http://dx.doi.org/10.1182/blood-2004-12-4603.
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AbstractMultipotent adult progenitor cells (MAPCs) are bone marrow-derived stem cells that have extensive in vitro expansion capacity and can differentiate in vivo and in vitro into tissue cells of all 3 germinal layers: ectoderm, mesoderm, and endoderm. The origin of MAPCs within bone marrow is unknown. MAPCs are believed to be derived from the bone marrow stroma compartment as they are isolated within the adherent cell component. Numerous studies of bone marrow chimeras in the human and the mouse point to a host origin of bone marrow stromal cells. Mesenchymal stem cells (MSCs), which coexist with stromal cells, have also been proven to be of host origin after allogeneic bone marrow transplantation in numerous studies. We report here that following syngeneic bone marrow transplants into lethally irradiated C57BL6 mice, MAPCs are of donor origin.
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Krambs, Joseph R., Grazia Abou Ezzi, Juo-Chin Yao, Justin T. Li, and Daniel C. Link. "Canonical Signaling By TGF Family Members in Mesenchymal Stromal Cells Is Dispensable for Hematopoietic Niche Maintenance Under Basal and Stress Conditions." Blood 134, Supplement_1 (November 13, 2019): 1209. http://dx.doi.org/10.1182/blood-2019-128693.
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The bone marrow contains a complex population of stromal and hematopoietic cells that together generate a unique microenvironment, or niche, to support hematopoiesis. Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche and include CXCL12-abundant reticular (CAR) cells, adipocytes, osteolineage cells, and arteriolar pericytes, all of which have been implicated in hematopoietic stem/progenitor cell (HSPC) maintenance. There also is evidence that adaptive changes in bone marrow stromal cells contributes to recovery from myelosuppresive therapy and the development of certain hematopoietic malignancies. However, the signals that contribute to the development, maintenance, and stress response of bone marrow mesenchymal stromal cells are poorly understood. Here, we test the hypothesis that cytokines of the transforming growth factor superfamily, which include bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and activins/inhibins, provide signals to mesenchymal stromal cells that contribute to basal and stress hematopoiesis responses. To test this hypothesis, we abrogated canonical TGF family signaling in mesenchymal stem/progenitor cells by deleting Smad4 using a doxycycline-repressible Osterix-Cre transgene (Osx-Cre), which targets all mesenchymal stromal cells in the bone marrow. We first performed lineage-tracing studies using Osx-Cre Smad4fl/fl Ai9 mice to show that activation of Osx-Cre at birth (by removal of doxycycline) results in the efficient targeting of bone marrow mesenchymal stromal cells. Moreover, we show that Smad4 mRNA expression is essentially undetectable in sorted mesenchymal stromal cells sorted from the bone marrow of these mice. Basal hematopoiesis and bone marrow stromal cells were analyzed in 6-8 week old Osx-Cre Smad4fl/fl mice. No alterations in the number or spatial organization of CAR cells, osteoblasts, or adipocytes was observed, and expression of key niche factors, including Scf, Cxcl12, and Spp1 was normal. Basal hematopoiesis, including the number of phenotypic HSCs in bone marrow and spleen, also was normal. Recent studies have shown that inhibition of activin signaling by treating with an activin receptor 2 alpha (ACVR2a) ligand trap stimulates erythropoiesis. Although ACVR2a signaling in erythroid progenitors contributes to this effect, two groups showed that inhibition of ACVR2a signaling in bone marrow stromal cells also stimulates erythropoiesis. Thus, we next characterized basal and stress erythropoiesis in Osx-Cre Smad4fl/fl mice. The frequency of phenotypic erythroid progenitors in bone marrow and spleen was similar to control mice. The stress erythropoiesis response was assessed after induction of acute hemolytic anemia by phenylhydrazine treatment. Both the magnitude of anemia and kinetics of erythroid recovery were similar to control mice. Myelosuppressive therapy induces marked alterations in the bone marrow microenvironment that includes an expansion of osteolineage cells and adipocytes, which have been linked to hematopoietic recovery. Thus, we next characterized stress hematopoiesis in Osx-Cre Smad4fl/fl mice in response to 5-fluorouracil (5-FU) treatment. Compared to control mice, the magnitude and duration of neutropenia following 5-FU were similar. Moreover, mouse survival after repeated weekly doses of 5-FU was comparable to control mice. HSPC mobilization by G-CSF is due, in large part, by downregulation of CXCL12 expression in bone marrow mesenchymal stromal cells. A prior study suggested that SMAD signaling negatively regulates CXCL12 expression in stromal cells. Consistent with this finding, we show that treatment of cultured bone marrow derived MSCs with TGF-b1 for 48 hours results in a significant (3.3-fold, P<0.0001) decrease in CXCL12 mRNA expression. Thus, in the final experiments, we characterized G-CSF induced HSPC mobilization in Osx-Cre, Smad4fl/fl or Osx-Cre, Tgfbr2fl/fl mice. HSPC mobilization, as quantified by CFU-C and Kit+ Sca+ lineage- (KSL) cell number in blood or spleen after 5 days of G-CSF treatment was comparable to control mice. Collectively, these data suggest the TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions. Disclosures No relevant conflicts of interest to declare.
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del Carmen Rodríguez, María, Antonio Bernad, and Miguel Aracil. "Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support." Blood 103, no. 9 (May 1, 2004): 3349–54. http://dx.doi.org/10.1182/blood-2003-10-3438.
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Abstract Interleukin-6 (IL-6) is a critical factor in the regulation of stromal function and hematopoiesis. In vivo bromodeoxyuridine incorporation analysis indicates that the percentage of Lin-Sca-1+ hematopoietic progenitors undergoing DNA synthesis is diminished in IL-6-deficient (IL-6-/-) bone marrow (BM) compared with wild-type BM. Reduced proliferation of IL-6-/- BM progenitors is also observed in IL-6-/- long-term BM cultures, which show defective hematopoietic support as measured by production of total cells, granulocyte macrophage-colony-forming units (CFU-GMs), and erythroid burst-forming units (BFU-Es). Seeding experiments of wild-type and IL-6-/- BM cells on irradiated wild-type or IL-6-deficient stroma indicate that the hematopoietic defect can be attributed to the stromal and not to the hematopoietic component. In IL-6-/- BM, stromal mesenchymal precursors, fibroblast CFUs (CFU-Fs), and stroma-initiating cells (SICs) are reduced to almost 50% of the wild-type BM value. Moreover, IL-6-/- stromata show increased CD34 and CD49e expression and reduced expression of the membrane antigens vascular cell adhesion molecule-1 (VCAM-1), Sca-1, CD49f, and Thy1. These data strongly suggest that IL-6 is an in vivo growth factor for mesenchymal precursors, which are in part implicated in the reduced longevity of the long-term repopulating stem cell compartment of IL-6-/- mice. (Blood. 2004;103:3349-3354)
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Widera, Darius. "Recent Advances in Translational Adipose-Derived Stem Cell Biology." Biomolecules 11, no. 11 (November 9, 2021): 1660. http://dx.doi.org/10.3390/biom11111660.
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Miura, Yasuo, Tatsuo Ichinohe, and Taira Maekawa. "Human Mesenchymal Stromal/Stem Cell-Mediated Bone Marrow Organization." Japanese Journal of Transfusion and Cell Therapy 61, no. 5 (2015): 489–90. http://dx.doi.org/10.3925/jjtc.61.489.
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Lim, Hong Kiat, Pravin Periasamy, and Helen C. O’Neill. "In Vitro Murine Hematopoiesis Supported by Signaling from a Splenic Stromal Cell Line." Stem Cells International 2018 (December 25, 2018): 1–9. http://dx.doi.org/10.1155/2018/9896142.
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There are very few model systems which demonstrate hematopoiesis in vitro. Previously, we described unique splenic stromal cell lines which support the in vitro development of hematopoietic cells and particularly myeloid cells. Here, the 5G3 spleen stromal cell line has been investigated for capacity to support the differentiation of hematopoietic cells from progenitors in vitro. Initially, 5G3 was shown to express markers of mesenchymal but not endothelial or hematopoietic cells and to resemble perivascular reticular cells in the bone marrow through gene expression. In particular, 5G3 resembles CXCL12-abundant reticular cells or perivascular reticular cells, which are important niche elements for hematopoiesis in the bone marrow. To analyse the hematopoietic support function of 5G3, specific signaling pathway inhibitors were tested for the ability to regulate cell production in vitro in cocultures of stroma overlaid with bone marrow-derived hematopoietic stem/progenitor cells. These studies identified an important role for Wnt and Notch pathways as well as tyrosine kinase receptors like c-KIT and PDGFR. Cell production in stromal cocultures constitutes hematopoiesis, since signaling pathways provided by splenic stroma reflect those which support hematopoiesis in the bone marrow.
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Muraglia, A., R. Cancedda, and R. Quarto. "Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model." Journal of Cell Science 113, no. 7 (April 1, 2000): 1161–66. http://dx.doi.org/10.1242/jcs.113.7.1161.
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Bone marrow stromal cells can give rise to several mesenchymal lineages. The existence of a common stem/progenitor cell, the mesenchymal stem cell, has been proposed, but which developmental stages follow this mesenchymal multipotent progenitor is not known. Based on experimental evidence, a model of mesenchymal stem cell differentiation has been proposed in which individual lineages branch directly from the same progenitor. We have verified this model by using clonal cultures of bone marrow derived stromal fibroblasts. We have analyzed the ability of 185 non-immortalized human bone marrow stromal cell clones to differentiate into the three main lineages: osteo-, chondro- and adipogenic. All clones but one differentiated into the osteogenic lineage. About one third of the clones differentiated into all three lineages analyzed. Most clones (60-80%) displayed an osteo-chondrogenic potential. We have never observed clones with a differentiation potential limited to the osteo-adipo- or to the chondro-adipogenic phenotype, nor pure chondrogenic and adipogenic clones. How long the differentiation potential of a number of clones was maintained was assessed throughout their life span. Clones progressively lost their adipogenic and chondrogenic differentiation potential at increasing cell doublings. Our data suggest a possible model of predetermined bone marrow stromal cells differentiation where the tripotent cells can be considered as early mesenchymal progenitors that display a sequential loss of lineage potentials, generating osteochondrogenic progenitors which, in turn, give rise to osteogenic precursors.
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Abou Ezzi, Grazia, Teerawit Suparkorndej, Bryan Anthony, Jingzhu Zhang, Shilpi Ganguly, Roberto Civitelli, and Daniel C. Link. "Loss of TGF-β Signaling in Bone Marrow Mesenchymal Progenitors Promotes Adipocyte over Osteoblast Differentiation but Does Not Disrupt the HSC Niche." Blood 126, no. 23 (December 3, 2015): 666. http://dx.doi.org/10.1182/blood.v126.23.666.666.
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Abstract Hematopoietic stem cells (HSCs) reside in specialized microenvironments (niches) in the bone marrow. Several mesenchymal stromal cells have been implicated in hematopoietic niches, including osteoblasts, pericytes, CXCL12-abundant reticular (CAR) cells, and mesenchymal stem cells (MSCs). Members of the transforming growth factor (TGF) superfamily, in particular TGF-β, have a well-documented role in regulating osteoblast development. However, the contribution of TGF family member signaling to the establishment and maintenance of hematopoietic niches is largely unknown. Here, we characterize the role of transforming growth factor-β (TGF-β) signaling in mesenchymal stromal cells on the HSC niche. TGF-β receptor 2 (encoded by Tgfbr2) is required for all TGF-β signaling. To selectively disrupt TGF-β signaling in bone marrow mesenchymal stromal cells, we generated Osx-C re Tgfbr2fl/fl mice. Osx-Cre targets most bone marrow mesenchymal stromal cells (including osteoblasts, CAR cells, MSCs, pericytes, and adipocytes) but not endothelial cells or hematopoietic cells. Osx-C re Tgfbr2fl/fl mice are severely runted and most die by 4 weeks of age. We analyzed mice at 3 weeks, when the mice appeared healthy. Osteoblast number was severely reduced in Osx-C re Tgfbr2fl/fl mice, as assessed by histomorphometry and immunostaining for osteocalcin. Accordingly, microCT analysis demonstrated reduced tissue mineral density and cortical thickness of long bone and marked trabecularization of long bones in diaphyseal regions. Surprisingly, marrow adiposity, as measured by osmium tetroxide staining with microCT, was strikingly increased in Osx-C re Tgfbr2fl/fl mice. CAR cells are mesenchymal progenitors with osteogenic and adipogenic potential in vitro. To assess CAR cells, we generated Osx-Cre Tgfrb2fl/fl x Cxcl12gfp mice. Surprisingly, CAR cell number was significantly increased. However, despite the increase in CAR cells, the number of CFU-osteoblast (CFU-OB) in Osx-C re Tgfbr2fl/fl mice is nearly undetectable. Together, these data suggest that TGF-b signaling contributes to lineage commitment of mesenchymal progenitors. Specifically, our data suggest that TGF-β signaling suppresses commitment to the osteoblast lineage, while increasing adipogenic differentiation. We next asked whether alterations in bone marrow stromal cells present in Osx-C re Tgfbr2fl/fl mice affect HSC number or function. The increase in marrow adipocytes and loss of osteolineage cells is predicted to impair HSC maintenance, while the increase in CAR cells might augment HSCs. Osx-Cre Tgfrb2fl/fl mice have modest leukopenia, but normal red blood cell and platelet counts. Bone marrow and spleen cellularity are reduced, even after normalizing for body weight. The frequency of phenotypic HSCs (defined as Kit+ lineage- Sca+ CD34- Flk2- cells) is comparable to control mice. To assess HSC function, we performed competitive repopulation assays with bone marrow from Osx-Cre Tgfrb2fl/fl or control mice. Surprisingly, these data show that the long-term multi-lineage repopulating activity of HSCs from Osx-Cre Tgfrb2fl/fl mice is normal. Moreover, serial transplantation studies suggest that the self-renewal capacity of HSCs is normal. Thus, despite major alterations in mesenchymal stromal cell populations, the HSC niche is intact in Osx-Cre Tgfrb2fl/fl mice. Collectively, these data show that TGF-b signaling in mesenchymal progenitors is required for the proper development of multiple stromal cell populations that contribute to hematopoietic niches. Studies are underway to assess the impact of post-natal deletion of Tgfbr2 in mesenchymal stromal cell on hematopoietic niches. Since drugs that modulate the activity of TGF-b are in development, this research may suggest novel approaches to modulate hematopoietic niches for therapeutic benefit. Disclosures No relevant conflicts of interest to declare.
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de Jong, Madelon M. E., Zoltan Kellermayer, Natalie Papazian, M. Duin, Annemiek Broyl, Pieter Sonneveld, and Tom Cupedo. "Single Cell Transcriptomic Analysis of the Multiple Myeloma Bone Marrow Identifies a Unique Inflammatory Stromal Cell Population Associated with TNF Signaling." Blood 134, Supplement_1 (November 13, 2019): 690. http://dx.doi.org/10.1182/blood-2019-123012.
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Background: In multiple myeloma, tumor cell survival, disease progression and therapy response are influenced by signals derived from the non-malignant bone marrow niche. This notwithstanding, a detailed in-vivo definition of the cells that define the multiple myeloma niche is lacking. Mesenchymal stromal cells are important niche constituents. Recent progress made with single cell transciptomics suggests that mesenchymal stromal cells are a dynamic population of cells that can exist as several subsets with functionally distinct activation and differentiation profiles. Aim: To identify mesenchymal stromal cell subsets specific for the multiple myeloma bone marrow niche, by comparing stromal cells from myeloma patients to non-cancer controls. Methods: The non-hematopoietic bone marrow niche was isolated from viably frozen bone marrow aspirates from 10 newly diagnosed multiple myeloma patients (6 hyperdiploid, 3 t(11;14) and 1 with deletion of 17p) and 2 non-cancer controls using high speed cell sorting. The purified cells were analyzed by 10X Genomics single cell sequencing directly post-thawing, without prior cell culture. From 10 multiple myeloma patients we generated single cell transcriptomes with an average read-depth of 20,000 reads per cell of in total 12,000 niche cells and from the 2 non-cancer controls a total of 3,500 niche cells. Transcriptomes were pooled and subjected to clustering analyses using the Seurat package for R to identify genetically distinct clusters of niche cells and changes in these clusters associated specifically with multiple myeloma. Results: The bioinformatical analyses generated 10 distinct clusters of niche cells, all of which were present in both non-cancer and multiple myeloma bone marrow. One of these clusters contained CDH5+ endothelial cells while the remaining 9 clusters were subsets of CXCL12+LEPR+ mesenchymal stromal cells. Because samples were taken from the central marrow by aspiration, peripheral endosteal or neuronal lineage cells were not represented in these clusters. Gene Set Enrichment Analysis (GSEA) of the stromal cell clusters from myeloma versus non-cancer controls revealed two significantly altered pathways: TNF signaling via NF-kB and Inflammatory response. Detailed analyses of the individual stromal cell clusters identified two clusters that were responsible for the inflammatory changes identified by GSEA. Both clusters were present in all myeloma patients, constituted on average 20% of total stromal cells and were defined by transcription of the inflammatory chemokines CXCL2, CXCL3 and CXCL8 the cytokine IL6. All these transcripts were absent from the equivalent clusters in control bone marrow. The presence of inflammatory stroma in the multiple myeloma niche indicates either the appearance of a novel stromal cell subset, or activation of pre-existing stromal cells. GSEA analyses suggested inflammatory signaling, and to functionally confirm this, we tested whether activation of stromal cells would induce the inflammatory stromal phenotype. Stimulation of primary human stromal cells in vitro with recombinant TNF was sufficient to induce transcription of CXCL2, CXCL3 and CXCL8, recapitulating the inflammatory transcriptome. Moreover, manual removal of these TNF target genes from the in-silico clustering analyses led to a merging of the inflammatory clusters with non-inflammatory clusters. This indicates that the major distinguishing feature of the myeloma-specific stromal cells are genes induced upon stromal cell activation. Conclusion: Through single cell transcriptomic analyses we have identified the presence of activated inflammatory stromal cells associated with TNF signaling in the multiple myeloma stromal niche. These inflammatory stromal cells are reminiscent of pathogenic cancer-associated fibroblasts found in solid tumors, where these cells create a pro-tumorigenic niche that favors tumor survival and proliferation while simultaneously inhibiting anti-cancer immunity. These findings represent the first description of myeloma-specific stromal cell subsets, and provide novel cellular targets for interventions aimed at disrupting the pro-tumorigenic microenvironment in multiple myeloma. Disclosures Broyl: Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding.
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Bhatia, R., PB McGlave, GW Dewald, BR Blazar, and CM Verfaillie. "Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages." Blood 85, no. 12 (June 15, 1995): 3636–45. http://dx.doi.org/10.1182/blood.v85.12.3636.bloodjournal85123636.
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The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC-IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth-inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14-cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14-mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.
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Kuznetsov, Sergei A., Mara Riminucci, Navid Ziran, Takeo W. Tsutsui, Alessandro Corsi, Laura Calvi, Henry M. Kronenberg, Ernestina Schipani, Pamela Gehron Robey, and Paolo Bianco. "The interplay of osteogenesis and hematopoiesis." Journal of Cell Biology 167, no. 6 (December 20, 2004): 1113–22. http://dx.doi.org/10.1083/jcb.200408079.
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The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo in mice expressing constitutively active parathyroid hormone/parathyroid hormone–related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.
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Yao, Juo-Chin, and Daniel C. Link. "TGF-β Signaling in Stromal Cells Contributes to Myelofibrosis, but Not Niche Disruption, in Myeloproliferative Neoplasms." Blood 138, Supplement 1 (November 5, 2021): 1463. http://dx.doi.org/10.1182/blood-2021-148776.
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Abstract Myeloproliferative neoplasms are associated with significant alterations in the bone marrow microenvironment that contribute to disease pathogenesis. The most striking alteration is the development of myelofibrosis, which is characterized by extensive collagen deposition in the bone marrow and is associated with a poor prognosis. Recent evidence suggests that expression of key niche factors, including CXCL12 (stromal derived factor-1, SDF-1) and Kit ligand are reduced in MPNs. This is relevant, since studies by our group and others have shown that deleting these niche factors from stromal cells results in a shift in hematopoiesis from the bone marrow to spleen. Indeed, a prominent feature of MPN is the development of splenomegaly and extramedullary hematopoiesis. There is evidence implicating inflammatory mediators in the development of myelofibrosis. In particular, increased production of TGF-β produced by megakaryocytes and monocytes is found in most patients with MPNs. To assess the role of TGF-β signaling in mesenchymal stromal cells in the bone marrow in the development of myelofibrosis, we generated Osx-Cre; Tgfbr2 f/- mice, in which TGF-β signaling is abrogated in all bone marrow mesenchymal stromal cells (including Lepr + stromal cells), but not endothelial cells or hematopoietic cells. We transplanted MPL W515L transduced hematopoietic stem and progenitor cells (HSPCs) or JAK2 V617F bone marrow into these mice and quantified myelofibrosis using reticulin staining and Collagen 1 and 3 immunostaining. We previously reported that deletion of TGF-β signaling in mesenchymal stromal cells in these mice abrogated the development of myelofibrosis, and we presented evidence that this was mediated by non-canonical JNK-dependent TGF-β signaling. Here, we describe the impact of stromal TGF-β signaling on the bone marrow hematopoietic niche in MPN. MPL W515L transduced HSPCs were transplanted into Osx-Cre; Tgfbr2 f/- mice, and the impact on hematopoietic niche disruption and development of extramedullary hematopoiesis was assessed. In control recipients, transplantation of MPL W515L HSPCs resulted in marked decreases in bone marrow Cxcl12 and Kit ligand expression (Figure 1A-B). Surprisingly, a similar decrease was observed in Osx-Cre; Tgfbr2 f/- recipients. The loss of these key niche factors is predicted to impair hematopoietic niche function in the bone marrow. Consistent with this prediction, total bone marrow cellularity and HSC number were significantly reduced in both control and Osx-Cre; Tgfbr2 f/- recipients (Figure 1C-D). Finally, disruption of the bone marrow niche is often associated with extramedullary hematopoiesis. Indeed, a significant increase in spleen size and spleen HSCs and erythroid progenitors was observed in control recipients (Figure 1E-G). Again, a similar phenotype was observed in Osx-Cre; Tgfbr2 f/- recipients. Collectively, these data show that TGF-β signaling in bone marrow mesenchymal stromal cells is required for the development of myelofibrosis but not hematopoietic niche disruption in MPNs. Thus, these data show for the first time that the signals that induce a fibrogenic program in bone marrow mesenchymal stromal cells are distinct from those that suppress Cxcl12 and Kit ligand expression. Our data show that the fibrogenic program is dependent on non-canonical JNK-dependent TGF-β signaling, while the signals that regulate niche factor expression remain unknown. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Basu, Soumit K., Xin Zhao, Sylvia Chien, Min Fang, Vivian Oehler, and Pamela S. Becker. "Characterization of Mesenchymal Stromal Cells (MSCs) Derived From Acute Myeloid Leukemia (AML) Bone Marrow." Blood 118, no. 21 (November 18, 2011): 2558. http://dx.doi.org/10.1182/blood.v118.21.2558.2558.
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Abstract Abstract 2558 INTRODUCTION Recent evidence has implicated the bone marrow microenvironment directly in the pathogenesis of preleukemic bone marrow disorders (Raaijmakers MHGP et al, Nature 2010) with potential to transform to AML. Moreover, the bone marrow microenvironment is critical to AML survival (Garrido et al 2001, Meads et al 2008). We sought to investigate aspects of the bone marrow microenvironment which may contribute to the pathogenesis and persistence of AML by direct analysis of primary bone marrow MSCs isolated from AML patients in comparison with primary bone marrow MSCs from normal subjects. Our analyses included (1) a comparison of cytokine elaboration between normal and AML bone marrow MSCs (2) immunophenotyping of normal and AML bone marrow MSCs (3) characterisation of binding by AML cells to their autologous stroma and (4) gene expression profiling of normal and AML bone marrow MSCs and (5) cytogenetic analysis AML bone marrow MSCs. METHODS We have been able to derive confluent cultures of mesenchymal stromal cells from 80% of AML patient marrow samples. Fresh or cryopreserved bone marrow samples were plated in non-hematopoietic expansion media (Miltenyi) under reduced oxygen conditions. After 48 hours of culture, nonadherent cells are removed, and over a period of 1–2 weeks, cultures of spindle shaped cells are derived, that can be sustained in culture for up to 5 passages. Similar cultures were derived from normal bone marrow. Gene expression profiling of bone marrow MSCs was performed by whole genome analysis using Illumina's BeadChip microarray platform. Samples included mRNAs isolated from confluent cultures of AML bone marrow MSCs, normal bone marrow MSCs, and the normal bone marrow stromal cell lines HS27a and HS5. RESULTS Comparison of cytokine elaboration showed a statistically significant (p = 0.037) 5-fold decrease in stromal MCP-1 production by AML bone marrow MSCs compared with normal bone marrow MSCs (327 ± 169 vs. 1669 ± 570 pg/mL, mean ± SE). Normal and AML MSCs showed no statistically significant differences in the production of G-CSF, GM-CSF, M-CSF, IL6, IL12, SCF, TNFα, MCP1 and SDF1β. Like their normal counterparts, AML bone marrow MSCs strongly express CD90, CD29 (β1 integrin), CD73, CD105, CD146, and CD44. The normal bone marrow derived stromal cell lines HS27a and HS5 demonstrated moderate expression of CD324/E-cadherin (28.4% and 37.9% respectively). E-cadherin expression proved highly variable among normal bone marrow MSCs (1.9%-54.9%) and similarly variable in AML bone marrow MSCs (7.8%–56.5%). AML binding to autologous MSCs primarily dependent on β1 integrin, L-selectin and VCAM-1. In contrast, prior data (Basu et al., ASH 2010 Abstract 2756) demonstrated AML binding to the normal bone marrow stromal cell line HS27a as primarily dependent on β1 integrin, CXCR4, and E-cadherin. Gene expression profiling demonstrated no significant differences between 6 AML and 5 normal bone marrow MSCs. AML bone marrow MSCs, as expected, demonstrated marked differences from AML bone marrow mononuclear cells, expressing higher levels of connective tissue growth factor (128 fold), tropomyosin 1 (84.4 fold), collagen type 1 α1 (194 fold), collagen type 1 α2 (137 fold), collagen type 4 α1 (128 fold), collagen type 5 α1 (119 fold), transgelin (111 fold), cadherin 11 (21 fold), biglycan (137 fold), IGF binding protein 6 (18 fold), and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (74 fold). In our cytogenetic analyses of MSCs to date, bone marrow MSCs derived from one of the complex karyotype AML patients demonstrated normal cytogenetics. In contrast, bone marrow MSCs derived from a second AML patient shared a common t(2;11) translocation present in the AML cells but demonstrated an abnormal clone with del(4q) which lacked the t(6;9) also present in the AML cells [i.e.-MSC karyotype: t(2;11), del(4q); AML karyotype: t(2;11), t(6;9)]. These results suggest that in some patients AML cells and their autologous MSCs may share the same clonal origin, while in other cases, the MSCs may have a distinct origin. CONCLUSION AML and normal bone marrow MSCs demonstrate only subtle differences, providing an explanation of the ability of AML bone marrow MSCs to support normal hematopoiesis after leukemic debulking (e.g. via induction chemotherapy or allogeneic stem cell transplant). Disclosures: No relevant conflicts of interest to declare.
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Chateauvieux, Sebastien, Jean-Laurent Ichanté, Bruno Delorme, Vincent Frouin, Geneviève Piétu, Alain Langonné, Nathalie Gallay, et al. "Molecular profile of mouse stromal mesenchymal stem cells." Physiological Genomics 29, no. 2 (April 2007): 128–38. http://dx.doi.org/10.1152/physiolgenomics.00197.2006.
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We determined a transcriptional profile specific for clonal stromal mesenchymal stem cells from adult and fetal hematopoietic sites. To identify mesenchymal stem cell-like stromal cell lines, we evaluated the adipocytic, osteoblastic, chondrocytic, and vascular smooth muscle differentiation potential and also the hematopoietic supportive (stromal) capacity of six mouse stromal cell lines from adult bone marrow and day 14.5 fetal liver. We found that two lines were quadripotent and also supported hematopoiesis, BMC9 from bone marrow and AFT024 from fetal liver. We then ascertained the set of genes differentially expressed in the intersection set of AFT024 and BMC9 compared with those expressed in the union set of two negative control lines, 2018 and BFC012 (both from fetal liver); 346 genes were upregulated and 299 downregulated. Using Ingenuity software, we found two major gene networks with highly significant scores. One network contained downregulated genes that are known to be implicated in osteoblastic differentiation, proliferation, or transformation. The other network contained upregulated genes that belonged to two categories, cytoskeletal genes and genes implicated in the transcriptional machinery. The data extend the concept of stromal mesenchymal stem cells to clonal cell populations derived not only from bone marrow but also from fetal liver. The gene networks described should discriminate this cell type from other types of stem cells and help define the stem cell state.
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Gang, Eun J., Darko Bosnakovski, Camila A. Figueiredo, Jan W. Visser, and Rita C. R. Perlingeiro. "SSEA-4 identifies mesenchymal stem cells from bone marrow." Blood 109, no. 4 (October 24, 2006): 1743–51. http://dx.doi.org/10.1182/blood-2005-11-010504.
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Abstract Adult bone marrow (BM) contains hematopoietic stem cells (HSCs) as well as a nonhematopoietic, stromal cell population. Within this stromal population are mesenchymal stem cells (MSCs), which not only support hematopoiesis but also differentiate into multiple lineages, including fat, bone, and cartilage. Because of this multipotentiality, the MSC is an attractive candidate for clinical applications to repair or regenerate damaged tissues of mesenchymal origin. However, research progress has been hampered by the limited existing knowledge of the biology of these cells, particularly by the lack of a suitable marker for their prospective isolation. Here, we report that SSEA-4, an early embryonic glycolipid antigen commonly used as a marker for undifferentiated pluripotent human embryonic stem cells and cleavage to blastocyst stage embryos, also identifies the adult mesenchymal stem cell population.
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Arai, Fumio, Osamu Ohneda, Takeshi Miyamoto, Xiu Qin Zhang, and Toshio Suda. "Mesenchymal Stem Cells in Perichondrium Express Activated Leukocyte Cell Adhesion Molecule and Participate in Bone Marrow Formation." Journal of Experimental Medicine 195, no. 12 (June 17, 2002): 1549–63. http://dx.doi.org/10.1084/jem.20011700.
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Perichondrium in fetal limb is composed of undifferentiated mesenchymal cells. However, the multipotency of cells in this region and the role of perichondrium in bone marrow formation are not well understood. In this report, we purified and characterized perichondrial cells using a monoclonal antibody against activated leukocyte cell adhesion molecule (ALCAM) and investigated the role of perichondrial cells in hematopoietic bone marrow formation. ALCAM is expressed on hematopoietic cells, endothelial cells, bone marrow stromal cells, and mesenchymal stem cells and mediates homophilic (ALCAM–ALCAM)/heterophilic (ALCAM-CD6) cell adhesion. Here we show by immunohistochemical staining that ALCAM is expressed in perichondrium. ALCAM+ perichondrial cells isolated by FACS® exhibit the characteristics of mesenchymal stem cells. ALCAM+ cells can differentiate into osteoblasts, adipocytes, chondrocytes, and stromal cells, which can support osteoclastogenesis, hematopoiesis, and angiogenesis. Furthermore, the addition of ALCAM-Fc or CD6-Fc to the metatarsal culture, the invasion of the blood vessels to a cartilage was inhibited. Our findings indicate that ALCAM+ perichondrial cells participate in vascular invasion by recruiting osteoclasts and vessels. These findings suggest that perichondrium might serve as a stem cell reservoir and play an important role in the early development of a bone and bone marrow.
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Josson, Sajni, Starlette Sharp, Shian-Ying Sung, Peter A. S. Johnstone, Ritu Aneja, Ruoxiang Wang, Murali Gururajan, Timothy Turner, Leland W. K. Chung, and Clayton Yates. "Tumor-Stromal Interactions Influence Radiation Sensitivity in Epithelial- versus Mesenchymal-Like Prostate Cancer Cells." Journal of Oncology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/232831.
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HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancerARCaPEandARCaPMcells in an EMT model. CoculturedARCaPEorARCaPMcells with HS-27a, developed increased colony forming capacity and growth advantage, withARCaPEexhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment inARCaPEcells compared toARCaPMcells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in bothARCaPE- andARCaPM-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation.
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Matkins, Victoria, Virginia Camacho, Ashley Hoang, Sweta Patel, and Robert S. Welner. "Perturbations of Marrow Stromal Cell function during Acute Inflammation." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 106.09. http://dx.doi.org/10.4049/jimmunol.206.supp.106.09.
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Abstract Mesenchymal stromal cells (MSCs) reside in a complex network of blood cells and can differentiate into mature chondrocytes, osteoblasts, and adipocytes. This trilineage differentiation process is tightly regulated by intrinsic and extrinsic signals, leading to transcriptional programming of balanced lineage output. Inflammatory insults to this stromal homeostatic balance occur through the upregulation of activating cytokines. Pro-inflammatory cytokines’ impact on the hematopoietic lineage is well-defined, but similar impacts to stroma was lacking. To define these changes, we studied two well-characterized forms of inflammation: polyinosinic-polycytidylic acid (Poly(I:C)), that activates IFNα, and Lipopolysaccharide (LPS), that through TLR4 promotes IFNγ. Prior studies of inflammatory conditions show bone loss; therefore, we hypothesized that there will be an increase in the MSC pool to compensate for loss of bone maturation. Using flow cytometry and lineage tracing models for stroma, we phenotypically characterized the non-hematopoietic cells’ changes following perturbation. The lineage-specific Cre models used were stroma (Prx1), adipocytes (AdipoQ), and osteoblasts (OCN). Our data shows an increase in MSCs with decreases in osteoblasts and adipocytes with stimulation. Furthermore, we used reverse-phase protein array (RPPA) and cytokine arrays to map the signaling mechanisms and activated pathways. We found an increase in specifically MAPK pathway with an accompanying increase in cytokines linked to this pathways’ activation. Understanding changes in the bone marrow microenvironment during inflammation will allow for therapeutic intervention in mediating hematopoietic diseases such as leukemia.
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Shipunova, Irina Nikolaevna, D. A. Svinareva, T. V. Petrova, M. M. Ryashentsev, V. E. Mamonov, N. I. Drize, I. N. Shipunova, et al. "Formation of Bone and Foci of Ectopic Hemopoiesis at Joint Application of Calcium Scaffolds with Bone Marrow Cells or Cultivated Mesenchymal Stromal Cells." N.N. Priorov Journal of Traumatology and Orthopedics 16, no. 2 (June 15, 2009): 85–90. http://dx.doi.org/10.17816/vto200916285-90.
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Potential application of calcium scaffolds in combination with either bone marrow or adherent cell layers from long-term cultures containing mesenchymal stem cell for the induction of bone tissue growth was studied in mice. Two scaffolds, i.e. Osteoset® and Prodens® were tested on the model of ectopic grafting under the skin and renal capsule of mice. It was demonstrated that Prodens® and less effectively Osteoset® could be used for the induction of bone growth in combination with bone marrow cells but even more effectively in combination with cultivated mesenchymal stromal cells. Both the site of transplantation and preliminary induction of bone differentiation of stromal cells exerted a great influence upon the process of bone formation.
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Kagami, Hideaki, Hideki Agata, and Arinobu Tojo. "Bone marrow stromal cells (bone marrow-derived multipotent mesenchymal stromal cells) for bone tissue engineering: Basic science to clinical translation." International Journal of Biochemistry & Cell Biology 43, no. 3 (March 2011): 286–89. http://dx.doi.org/10.1016/j.biocel.2010.12.006.
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Ganguly, Payal, Jehan J. El-Jawhari, Peter V. Giannoudis, Agata N. Burska, Frederique Ponchel, and Elena A. Jones. "Age-related Changes in Bone Marrow Mesenchymal Stromal Cells." Cell Transplantation 26, no. 9 (September 2017): 1520–29. http://dx.doi.org/10.1177/0963689717721201.
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Aging at the cellular level is a complex process resulting from accumulation of various damages leading to functional impairment and a reduced quality of life at the level of the organism. With a rise in the elderly population, the worldwide incidence of osteoporosis (OP) and osteoarthritis (OA) has increased in the past few decades. A decline in the number and “fitness” of mesenchymal stromal cells (MSCs) in the bone marrow (BM) niche has been suggested as one of the factors contributing to bone abnormalities in OP and OA. It is well recognized that MSCs in vitro acquire culture-induced aging features such as gradual telomere shortening, increased numbers of senescent cells, and reduced resistance to oxidative stress as a result of serial population doublings. In contrast, there is only limited evidence that human BM-MSCs “age” similarly in vivo. This review compares the various aspects of in vitro and in vivo MSC aging and suggests how our current knowledge on rejuvenating cultured MSCs could be applied to develop future strategies to target altered bone formation processes in OP and OA.
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Jacamo, Rodrigo, Ye Chen, Zhiqiang Wang, Wencai Ma, Min Zhang, Venkata L. Battula, Wendy D. Schober, Richard E. Davis, Marina Konopleva, and Michael Andreeff. "NF-κB Activation in Mesenchymal Stromal Cells Mediates Leukemia Cell Chemoresistance." Blood 120, no. 21 (November 16, 2012): 3518. http://dx.doi.org/10.1182/blood.v120.21.3518.3518.
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Abstract Abstract 3518 Within the bone marrow (BM) microenvironment, BM mesenchymal stromal cells (BM-MSC) provide leukemia cells with a rich environment that serves as a sanctuary and protects them from chemotherapeutic agents. Interactions between leukemia cells and BM-MSC are thought to change the behavior of both stroma and leukemia cells resulting in an increased resistance to standard drugs. To discover interaction-induced changes in BM-MSCs that might promote microenvironment-mediated chemoresistance we used genome-wide gene expression profiling to study normal-donor BM-MSCs co-cultured with REH cells, a pre-B acute lymphoblastic leukemia (ALL) cell line. Upregulated genes in normal-donor BM-MSCs by co-culture included many cytokines and chemokines and implicated activation of NF-κB in BM-MSCs. Similar results were obtained by co-culturing normal-donor BM-MSCs with OCI-AML3 cells, an acute myeloid leukemia (AML) cell line. Increased expression of NF-κB target genes in BM-MSCs was also induced by co-culture with primary cells from ALL and AML patients, suggesting that NF-κB activation is a common consequence of leukemia-stroma interaction. Blocking canonical-pathway NF-κB activation by overexpressing a super-repressor form of IκBα in BM-MSC, significantly reduced stroma-mediated chemoresistance to vincristine (VCR) of leukemia cells in vitro and in vivo using an extramedullary bone marrow model. When small-molecule IKKβ inhibitors (MLN3316 and CDDO-Me) were used in co-cultures, blocking canonical-pathway NF-κB activation in ALL cell lines (REH or RS4;11) as well as BM-MSCs, the apoptotic effects of VCR on leukemia cells were further increased. Conclusion: results indicate that leukemia cells activate NF-κB in stromal cells and that such activation is in turn essential to promote survival of leukemia cells during chemotherapy. Targeting NF-κB in BM-MSC may ameliorate stroma-mediated chemoresistance and help in eliminating BM-resident leukemia cells. Disclosures: No relevant conflicts of interest to declare.
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Abou Ezzi, Grazia, Teerawit Supakorndej, Jingzhu Zhang, Joseph R. Krambs, Hamza Celik, and Daniel C. Link. "TGF-β Signaling in Fetal Mesenchymal Progenitor Cells Plays an Essential Role in the Emergence of Bone Marrow Hematopoietic Niches." Blood 132, Supplement 1 (November 29, 2018): 3847. http://dx.doi.org/10.1182/blood-2018-99-117396.
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Abstract Hematopoietic stem/progenitor cells (HSPC) reside in a unique microenvironment within the bone marrow called the bone marrow hematopoietic niche. Mesenchymal stromal cells, including CXCL12-abundant reticular (CAR) cells, osteoblasts, arteriolar pericytes, and adipocytes are all important components of the niche. The development and maintenance of mesenchymal stromal cells in the bone marrow is not well characterized. A prior study suggested that these stromal cells are derived from two distinct types of mesenchymal stem/progenitor cells (MSPCs). Primitive MSPCs are present in fetal bone and are responsible for osteoblasts, CAR cells, and adipocytes through approximately 3 weeks after birth, and definitive MPSCs are present at birth and generate bone marrow mesenchymal stromal cells in adult mice. In this study, we abrogated transforming growth factor-b (TGF-β) signaling in MSPCs by deleting Tgfbr2in mesenchymal cells using a doxycycline-repressible Sp7(osterix)-Cre transgene (Osx-Cre).We previously reported that loss of TGF-βsignaling during fetal development results in a marked expansion of CAR cells and adipocytes in the bone marrow, while osteoblasts are significantly reduced. These stromal alterations are associated with significant defects in hematopoiesis, including a shift from lymphopoiesis to myelopoiesis. However, hematopoietic stem cell function is preserved. Interestingly, TGF-βsignaling is dispensable for the maintenance of mesenchymal cells in the bone marrow after birth under steady state conditions. These data show that TGF-βplays an essential role in the lineage specification of fetal but not definitive MSPCs and is required for the establishment of normal hematopoietic niches in fetal and perinatal bone marrow. Canonical TGF-bsignaling is dependent on SMAD4. To investigate whether MSPC lineage specification by TGF-bis dependent on SMAD4, we generated Osx-Cre Smad4Δ/Δmice. Osx-Cre Smad4Δ/Δmice are runted to a similar degree as Osx-CreTgfbr2Δ/Δmice secondary to a loss of mature osteoblasts. However, the magnitude of the increase in bone marrow adiposity is significantly reduced in Osx-Cre Smad4∆/∆mice compared to Osx-Cre, Tgfbr2Δ/Δmice. These data suggested that non-canonical signaling contributes to the suppressive effect of TGF-b on adipogenesis. To test this hypothesis, we generated cultures of mesenchymal stromal cells from wildtype neonatal bone marrow. As expected, in wildtype cultures, the addition of TGF-bpotently suppressed adipocyte formation. To assess the role of MAPK activation on the suppression of adipogenesis by TGF-b, we pharmacologically inhibited MAPK activation. Inhibition of MAPK alone did not suppress adipocyte formation. However, it completely blocked the suppressive effect of TGF-bon adipogenesis. Prior studies showed that phosphorylation of serine 82 of PPARgby MAPK decreases its transcriptional activity. Since PPARgis a master regulator of adipogenesis, we assessed the ability of TGF-b to induce PPARgphosphorylation. Indeed, the addition of TGF-b to the MSPC cultures resulted in reproducible PPARgphosphorylation. These data suggest that TGF-b suppresses adipocyte specification of MSPCs, in part, in a MAPK-dependent fashion through phosphorylation of PPARg. In summary, our data suggest that TGF-b plays a key role in the lineage specification of fetal MSPCs during development and is required for the proper development of fetal hematopoietic niches in the bone marrow. The contribution of TGF-b signaling in MSPCs to the stromal and hematopoietic response to different stressors is an active area of investigation. Disclosures No relevant conflicts of interest to declare.
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Kojima, Kensuke, Teresa McQueen, Ye Chen, Rodrigo Jacamo, Marina Konopleva, Naoki Shinojima, Elizabeth Shpall, Xuelin Huang, and Michael Andreeff. "p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1α–mediated down-regulation of CXCL12." Blood 118, no. 16 (October 20, 2011): 4431–39. http://dx.doi.org/10.1182/blood-2011-02-334136.
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Abstract Fms-like tyrosine kinase-3 (FLT3) inhibitors have been used to overcome the dismal prognosis of acute myeloid leukemia (AML) with FLT3 mutations. Clinical results with FLT3 inhibitor monotherapy have shown that bone marrow responses are commonly less pronounced than peripheral blood responses. We investigated the role of p53 in bone marrow stromal cells in stromal cell-mediated resistance to FLT3 inhibition in FLT3 mutant AML. While the FLT3 inhibitor FI-700 induced apoptosis in FLT3 mutant AML cells, apoptosis induction was diminished under stromal coculture conditions. Protection appeared to be mediated, in part, by CXCL12 (SDF-1)/CXCR4 signaling. The protective effect of stromal cells was significantly reduced by pre-exposure to the HDM2 inhibitor Nutlin-3a. p53 activation by Nutlin-3a was not cytotoxic to stromal cells, but reduced CXCL12 mRNA levels and secretion of CXCL12 partially through p53-mediated HIF-1α down-regulation. Results show that p53 activation in stroma cells blunts stroma cell-mediated resistance to FLT3 inhibition, in part through down-regulation of CXCL12. This is the first report of Nutlin effect on the bone marrow environment. We suggest that combinations of HDM2 antagonists and FLT3 inhibitors may be effective in clinical trials targeting mutant FLT3 leukemias.
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Brinchmann, Jan E. "Expanding autologous multipotent mesenchymal bone marrow stromal cells." Journal of the Neurological Sciences 265, no. 1-2 (February 2008): 127–30. http://dx.doi.org/10.1016/j.jns.2007.05.006.
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Zhao, Guiyun, Huijiao Ji, Shihao Wang, Bin Gu, Xiuli Song, Jiarong Zhang, Yukan Liu, Liangbiao Chen, and Ming Zhang. "Cell Surface Proteomics Analysis Indicates a Neural Lineage Bias of Rat Bone Marrow Mesenchymal Stromal Cells." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/479269.
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Mesenchymal stromal cells (MSCs) are one of the most intensively studied stem cell types with application aims. However, the molecular characterisation and the relationship between the molecular characterisation and functional properties of MSCs are largely unknown. In this study, we purified the surface proteins from rat bone marrow MSCs (rBMMSCs) and characterised their surface proteome by LC-MS/MS. Moreover, we comparatively analysed the data from this study with the surface proteomics data of mouse and human embryonic stem (ES) cells and human mesenchymal stromal cells (hMSCs). The data showed that, in contrast to ES cells and human mesenchymal stromal cells, rBMMSCs possessed a surface proteomics pattern biased to neural and neural-endocrine lineages, indicating a neural/neural crest bias, and suggested a neural differentiation tendency of these cells. The different surface proteomics pattern between rBMMSCs and hMSCs also suggested that MSCs of different origin might possess a different lineage bias.
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PALL, Emoke, Ioan GROZA, Olga SORITAU, Ciprian TOMULEASA, Mihai CENARIU, Daria GROZA, and Teodora VLASIU. "RAT BONE MARROW MESENCHYMAL STEM CELLS ISOLATION, CULTIVATION AND DIFFERENTIATION." Cluj Veterinary Journal 15, no. 1 (March 16, 2009): 30–34. http://dx.doi.org/10.52331/cvj.v15i1.6.
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Bone marrow stromal cells (MSCs) represent a heterogeneous population derived from the non–blood-forming fraction of bone marrow that regulates hematopoietic cell development. In vitro, adult mesenchymal stem cells resident in this bone marrow fraction differentiate into bone, cartilage, and fat. Because MSCs can be easily obtained using a simple bone marrow aspiration and show extensive capacity for expansion in vitro, these cells have been considered as candidates for cell therapy. The aim of this study was to purify rat MSCs from adult bone marrow and to functionally characterise their abilities to differentiate along diverse lineages. Our data demonstrate that we successfully isolated, culture-expanded and differentiated a relatively homogeneous population of MPCs from adult rat bone marrow.
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Volkova, N. А. "MULTIPOTENT MESENCHYMAL STROMAL CELLS OF BONE MARROW IN THERAPY OF CHRONIC INFLAMMATION OF THE MURINE OVARIES." Biotechnologia acta 7, no. 5 (2014): 35–42. http://dx.doi.org/10.15407/biotech7.05.035.
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Oh, Il-Hoan, Kyong-Rim Kwon, Ji-Yeon Ahn, Myungshin Kim, and Jeong-Hwa Lee. "Disruption of Bis Leads to Deterioration of Mesenchymal Stromal Cells Predominantly Affecting Vascular Compartment of Hematopoietic Stem Cell Niche." Blood 114, no. 22 (November 20, 2009): 3627. http://dx.doi.org/10.1182/blood.v114.22.3627.3627.
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Abstract Abstract 3627 Poster Board III-563 The stem cell niche plays an important role in the microenvironmental regulation of hematopoietic stem cells (HSCs), but the integration of niche activity remains poorly understood. In this study explored the hematopoietic defect of mice disrupted with Bis/BAG-3/CAIR-1, a protein related to apoptosis and response to cellular stress and show that functional loss of bis leads to series of hematopoietic derangements due to perturbation of vascular stem cell niche. First, mice with targeted disruption of bis (bis−/−) exhibited severe hypocellularity in the bone marrows and spleen starting from 16 days after birth. Affected mice exhibited loss of primitive neonatal HSCs (CD34+Lin-Sca-1+c-kit+) and defect in early stage B-lymphopoiesis including common lymphoid progenitors (IL-17R+LSK), pre-B and pro-B cell populations, but not for mature recycling B-lymphocytes (IgD+B220+). However, this hematological defect of bis−/− mice was not reproduced when bis−/− bone marrow cells were transplanted into wild-type (WT) recipients, pointing to the microenvironmental origin of the phenotypes. Subsequent analysis of bis−/− mice bone marrow revealed a characteristic defect in the mesenchymal stromal component that included a quantitative loss of stromal cells (CD45-CD31-TER119-CD105+) in the bone marrows and rapid sensescence of stromal cells comprising colony forming unit-fibroblast (CFU-F) when re-plated in the ex-vivo culture. Moreover, mesenchymal stromal cells expressing CXCL-12 or IL-7 was lost in the affected bone marrows with lowered density of vascular development, together indicating a perturbation of peri-vascular stem cell niche in the bone marrow. In contrast, no abnormalities were observed in the growth and hematopoietic supporting activities of osteoblasts obtained from bis−/− mice. Collectively, these results indicate that Bis functions to mediate cellular regulation of the stem cell niche activities selectively on the vascular compartment without affecting osteoblastic niche, and suggest that Bis may serve as a molecule that can bridge the microenvironment niche and cellular stress/apoptotic signals during the in-vivo orchestration of hematopoiesis. Disclosures: No relevant conflicts of interest to declare.
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Westman, Amanda M., Rachel L. Goldstein, Gino Bradica, Scott M. Goldman, Mark A. Randolph, Joseph P. Gaut, Joseph P. Vacanti, and David M. Hoganson. "Decellularized extracellular matrix microparticles seeded with bone marrow mesenchymal stromal cells for the treatment of full-thickness cutaneous wounds." Journal of Biomaterials Applications 33, no. 8 (January 16, 2019): 1070–79. http://dx.doi.org/10.1177/0885328218824759.
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Extracellular matrix materials mechanically dissociated into submillimeter particles have a larger surface area than sheet materials and enhanced cellular attachment. Decellularized porcine mesothelial extracellular matrix microparticles were seeded with bone marrow-derived mesenchymal stromal cells and cultured in a rotating bioreactor. The mesenchymal stromal cells attached and grew to confluency on the microparticles. The cell-seeded microparticles were then encapsulated in varying concentrations of fibrin glue, and the cells migrated rapidly off the microparticles. The combination of microparticles and mesenchymal stromal cells was then applied to a splinted full-thickness cutaneous in vivo wound model. There was evidence of increased cell infiltration and collagen deposition in mesenchymal stromal cells-treated wounds. Cell-seeded microparticles have potential as a cell delivery and paracrine therapy in impaired healing environments.
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Zhang, Jingzhu, and Daniel C. Link. "Targeting Bone Marrow Mesenchymal Stromal Cells Using Cre-Recombinase Transgenes." Blood 126, no. 23 (December 3, 2015): 2401. http://dx.doi.org/10.1182/blood.v126.23.2401.2401.
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The bone marrow microenvironment contains hematopoietic niches that regulate the proliferation, differentiation, and trafficking of hematopoietic stem/progenitors cells (HSPCs). These hematopoietic niches are comprised of a heterogeneous population of stromal cells that include, endothelial cells, osteoblasts, CXCL12-abundant reticular (CAR) cells, mesenchymal stem cells (MSCs), arteriolar pericytes, and sympathetic nerves. Emerging data suggest that specific stromal populations may regulate distinct types of HPSCs. Thus, it is important to have validated approaches to interrogate and target specific stromal cell populations. Prior studies have shown that Prx1-Cre, Osx-Cre, Lepr-Cre, and Nes-Cre broadly target mesenchymal stromal cells in the bone marrow. Here, we rigorously define the stromal cell populations targeted by two Cre-transgenes that are commonly used to target osteolineage cells (Ocn-Cre, and Dmp1-Cre) and introduce a new Cre-transgene (Tagln-Cre) that efficiently targets bone marrow pericytes. For each Cre-transgene, we performed lineage mapping using ROSA26Ai9/Ai9 mice, in which cells that have undergone Cre-mediated recombination express tdTomato. In some cases, we further crossed these mice to introduce the Cxcl12gfp transgene, which can be used to define GFP-bright CAR cells. Immunostaining of bone sections and flow cytometry were used to define the target stromal cell population(s) in these mice. Osteocalcin (Bglap, Ocn) is primarily expressed in mature osteoblasts. Accordingly, Ocn-Cre is widely used to specifically target osteoblasts. However, our lineage mapping studies show that Ocn-Cre targets not only all osteoblasts, but also 72 ± 4.0% of CAR cells. Ocn-Cre also targets a subset of NG2+ arteriolar pericytes. Dentin matrix acidic phosphoprotein 1 (Dmp1) is expressed primarily in osteocytes, and Dmp1-Cre has been widely used to specifically target osteocytes. However, we show that Dmp1-Cre also efficiently targets endosteal osteoblasts and approximately 40% of CAR cells. To target bone marrow pericytes, we tested several Cre-transgenes, ultimately focusing on Tagln-Cre. Transgelin (Tagln, SM22a) is broadly expressed in pericytes, smooth muscle cells, and cardiomyocytes. Lineage-mapping studies show that Tagln-Cre targets all arteriolar and venous sinusoidal pericytes in the bone marrow. It also targets osteoblasts and 75 ± 5.2% of CAR cells. There are several recent studies that have ascribed specific functions to osteoblasts or osteocytes based on targeting using Ocn-Cre or Dmp1-Cre, respectively. In light of our data, these conclusions need to be re-evaluated. Ocn-Cre, Dmp1-Cre, and Tagln-Cre each target a subset of CAR cells. Studies are underway to determine whether these CAR subsets have unique expression profiles and functions. Finally, Talgn-Cre represents a new tool for investigators in the field to efficiently target bone marrow pericytes. Disclosures No relevant conflicts of interest to declare.
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Matkins, Victoria, Virginia Camacho, Ashley Hoang, Sweta Patel, and Robert S. Welner. "Perturbations of Marrow Stromal Cell function during Acute Inflammation." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 46.11. http://dx.doi.org/10.4049/jimmunol.208.supp.46.11.
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Abstract Mesenchymal stromal cells (MSCs) reside in a complex network of blood cells and can differentiate into chondrocytes, osteoblasts, and adipocytes. MSCs differentiation process is tightly regulated through intrinsic and extrinsic signals within the marrow microenvironment, leading to transcriptional programming of balanced lineage output. Inflammatory insults to this system can occur through the upregulation of activating cytokines. Pro-inflammatory cytokines’ impact on the hematopoietic lineage is well-defined, but similar impacts to stromal cells was largely undefined. To delineate these changes, we studied two well-characterized forms of inflammation: polyinosinic-polycytidylic acid (Poly(I:C)), that activates IFNα, and Lipopolysaccharide (LPS), that promotes IFNγ. Prior studies of inflammatory conditions showed bone loss; therefore, we hypothesized that there would be an increase in the MSC pool to compensate for loss of bone maturation. Using flow cytometry and lineage-tracing models of stroma, we characterize the non-hematopoietic cells’ changes following inflammatory perturbation. Our data show an increase in MSCs with decreases in osteoblasts and adipocytes following stimulation. Furthermore, we used reverse-phase protein and cytokine arrays to map the signaling mechanisms and activated pathways. We found an increase in the NFκB pathway with an accompanying increase IL-1β. Targeting of the IL-1 pathway did not phenotypically reverse the stromal perturbations but corrected the MSCs functionally. Understanding these alterations within the bone marrow microenvironment during inflammation will allow for therapeutic interventions to mediate hematopoietic diseases such as sepsis or leukemia. Supported by NIH R01 HL150078
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Yao, Qingping, James Wang, and Ram Raj Singh. "Bone Marrow Derived Mesenchymal Stromal Cells Promote Treg Cell Development Ex Vivo." Clinical Immunology 123 (2007): S106. http://dx.doi.org/10.1016/j.clim.2007.03.481.
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Sugrue, Tara, Noel F. Lowndes, and Rhodri Ceredig. "Mesenchymal stromal cells: radio‐resistant members of the bone marrow." Immunology & Cell Biology 91, no. 1 (November 20, 2012): 5–11. http://dx.doi.org/10.1038/icb.2012.61.
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Watt, Suzanne M., Sarah Hale, Dilair Baban, Maria Roubelakis, Meis Moukayed, Jaeseung Lim, Dacey J. Ryan, Kay Davies, Adrian L. Harris, and Enca Martin-Rendon. "The Centromeric Protein, CEN(P)-F, a Marker of Cell Proliferation Is Regulated by Hypoxia in Human Mesenchymal Stem Cells and Their Bone Marrow Stromal Progeny." Blood 106, no. 11 (November 16, 2005): 1385. http://dx.doi.org/10.1182/blood.v106.11.1385.1385.
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Abstract Human bone marrow mesenchymal stem cells (MSC) are multipotent progenitors that generate osteoblasts, chondrocytes, adipocytes, myoblasts and the bone marrow stromal cells that support hematopoiesis. Although the bone marrow microenvironment is hypoxic, little is known about the maintenance and response of MSC and their bone marrow stromal progeny to hypoxia. Using cDNA microarray hybridization technologies, we show, for the first time, that a total of 231 mRNAs in cultured MSCs are regulated by short exposures (4–48hrs) to hypoxia. These include known hypoxia-responsive genes, such as BHLHB2, PGK1, GLUT-1 and VEGF. Interestingly, we demonstrate that a significant proportion of genes involved in cell growth, proliferation or survival are also regulated by hypoxia in these cells. Amongst these, we have identified the centromeric protein CENP-F as a novel gene up-regulated in cultured MSCs by hypoxia. This up-regulation results in an increased level of CENP-F protein. The hypoxic stimulus also enhances cell division in the bone marrow MSC-derived stromal cells, resulting in a doubling in cell number within 24hrs. This contrasts with the effects of hypoxia on mature endothelial cells (EC), where recruitment into cell cycle is unchanged. Our demonstration that hypoxia promotes cell division and cell proliferation in the bone marrow stromal progeny of human MSC may have wider implications for the regulated growth and survival of other stem cells in hypoxic microenvironmental niches.
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Emmons, Russell, Grace M. Niemiro, Olatomide Owolabi, and Michael De Lisio. "Acute exercise mobilizes hematopoietic stem and progenitor cells and alters the mesenchymal stromal cell secretome." Journal of Applied Physiology 120, no. 6 (March 15, 2016): 624–32. http://dx.doi.org/10.1152/japplphysiol.00925.2015.
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Transplantation of hematopoietic stem and progenitor cells (HSPC), collected from peripheral blood, is the primary treatment for many hematological malignancies; however, variable collection efficacy with current protocols merits further examination into factors responsible for HSPC mobilization. HSPCs primarily reside within the bone marrow and are regulated by mesenchymal stromal cells (MSC). Exercise potently and transiently mobilizes HSPCs from the bone marrow into peripheral circulation. Thus the purpose of the present study was to evaluate potential factors in the bone marrow responsible for HSPC mobilization, investigate potential sites of HSPC homing, and assess changes in bone marrow cell populations following exercise. An acute exercise bout increased circulating HSPCs at 15 min (88%, P < 0.001) that returned to baseline at 60 min. Gene expression for HSPC homing factors (CXCL12, vascular endothelial growth factor-a, and angiopoietin-1) were increased at 15 min in skeletal muscle and HSPC content was increased in the spleen 48 h postexercise (45%, P < 0.01). Acute exercise did not alter HSPCs or MSCs quantity in the bone marrow; however, proliferation of HSPCs (40%, P < 0.001), multipotent progenitors (40%, P < 0.001), short-term hematopoietic stem cells (61%, P < 0.001), long-term hematopoietic stem cells (55%, P = 0.002), and MSCs (20%, P = 0.01) increased postexercise. Acute exercise increased the content of the mobilization agent granulocyte-colony stimulating factor, as well as stem cell factor, interleukin-3, and thrombopoeitin in conditioned media collected from bone marrow stromal cells 15 min postexercise. These findings suggest that the MSC secretome is responsible for HSPC mobilization and proliferation; concurrently, HSPCs are homing to extramedullary sites following exercise.
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Pillozzi, Serena, and Andrea Becchetti. "Ion Channels in Hematopoietic and Mesenchymal Stem Cells." Stem Cells International 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/217910.
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Hematopoietic stem cells (HSCs) reside in bone marrow niches and give rise to hematopoietic precursor cells (HPCs). These have more restricted lineage potential and eventually differentiate into specific blood cell types. Bone marrow also contains mesenchymal stromal cells (MSCs), which present multilineage differentiation potential toward mesodermal cell types. In bone marrow niches, stem cell interaction with the extracellular matrix is mediated by integrin receptors. Ion channels regulate cell proliferation and differentiation by controlling intracellular Ca2+, cell volume, release of growth factors, and so forth. Although little evidence is available about the ion channel roles in true HSCs, increasing information is available about HPCs and MSCs, which present a complex pattern of K+channel expression. K+channels cooperate with Ca2+and Cl−channels in regulating calcium entry and cell volume during mitosis. Other K+channels modulate the integrin-dependent interaction between leukemic progenitor cells and the niche stroma. These channels can also regulate leukemia cell interaction with MSCs, which also involves integrin receptors and affects the MSC-mediated protection from chemotherapy. Ligand-gated channels are also implicated in these processes. Nicotinic acetylcholine receptors regulate cell proliferation and migration in HSCs and MSCs and may be implicated in the harmful effects of smoking.
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Yao, Juo-Chin, Grazia Abou Ezzi, Joseph R. Krambs, Eric J. Duncavage, and Daniel C. Link. "TGF-Beta Signaling in Mesenchymal Stromal Cells Contributes to Myelofibrosis but Not Hematopoietic Phenotypes in Myeloproliferative Neoplasms." Blood 132, Supplement 1 (November 29, 2018): 3053. http://dx.doi.org/10.1182/blood-2018-99-113745.
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Abstract The development of myelofibrosis in patients with myeloproliferative neoplasms (MPNs) is associated with a dismal prognosis. The mechanisms responsible for the progression to myelofibrosis are unclear, limiting the development of therapies to treat or prevent it. The cell of origin responsible for the increased collagen deposition is controversial, with recent studies implicating Gli1+ or leptin receptor+ mesenchymal stromal cells, monocytes, or even endothelial cells. Moreover, the signals generated by malignant hematopoietic cells in MPN that induce increased collagen expression are uncertain. There is some evidence that elevated expression of cytokines/chemokines in the bone marrow microenvironment of patients with MPN may contribute. In particular, recent studies have implicated transforming growth factor-β (TGF-β), platelet-derived growth factor and CXCL4 in the development of myelofibrosis. Here, we test the specific hypothesis that TGF-β signaling in mesenchymal stromal cells is required for the development of myelofibrosis. Moreover, we hypothesize that TGF-β signaling, by altering the expression of key niche factors by mesenchymal stromal cells, contributes to the myeloid expansion in MPN. To test this hypothesis, we abrogated TGF-β signaling in mesenchymal stem/progenitor cells (MSPCs) by deleting Tgfbr2 using a doxycycline-repressible Sp7 (osterix)-Cre transgene (Osx-Cre), which targets all mesenchymal stromal cells in the bone marrow, including CXCL12-abundant reticular (CAR) cells, osteoblasts, adipocytes, or arteriolar pericytes. We previously showed that TGF-β signaling plays a key role in the lineage specification of MSPCs during development (2017 ASH abstract #2438). In contrast, we show that post-natal deletion of Tgfbr2, by removing doxycycline at birth, is not associated with significant changes in mesenchymal stromal cells in the bone marrow. Moreover, expression of key niche factors, including Cxcl12 and stem cell factor, and basal hematopoiesis were normal in these mice. Thus, we used the post-natal Osx-Cre; Tgfbr2-deleted mice as recipients to assess the role of TGF-β signaling in mesenchymal stromal cells on the hematopoietic and myelofibrosis phenotype in Jak2V617For MPLW515Lmodels of MPN. Specifically, we transplanted hematopoietic cells from Mx1-Cre; Jak2V617Fmice (4 weeks after pIpC treatment) or hematopoietic cells transduced with MPLW515Lretrovirus into irradiated wildtype or post-natal Osx-Cre; Tgfbr2-deleted mice. Both MPN models have elevated Tgfb1 expression in the bone marrow. As reported previously, transplantation of MPLW515Ltransduced hematopoietic cells into wildtype recipients produced a rapidly fatal MPN characterized by neutrophilia, erythrocytosis, thrombocytosis, splenomegaly, and reticulin fibrosis in the bone marrow. A similar hematopoietic phenotype was observed in Osx-Cre; Tgfbr2fl/flrecipients. However, a trend to decreased reticulin fibrosis was observed in Osx-Cre; Tgfbr2fl/flcompared to wildtype recipients (reticulin histology score: 0.5 versus 1.1, respectively, n=5, p=0.23). Likewise, the degree of neutrophilia, erythrocytosis, thrombocytosis, and splenomegaly in wildtype and Osx-Cre; Tgfbr2fl/flrecipients of Jak2V617Fcells was similar. As reported previously, we did not observe overt myelofibrosis in this model (as measured by reticulin staining). However, we were able to detect increased collagen III deposition using immunofluorescence staining in 4 of 5 wildtype recipients compared to 1 of 4 Osx-Cre Tgfbr2fl/flrecipients of Jak2V617Fcells (p=0.21). In conclusion, our data suggest that TGF-β signaling in mesenchymal stromal cells contributes, but is not absolutely required, for the development of myelofibrosis. Alterations in mesenchymal stromal cells induced by increased TGF-β signaling do not appear to be a major driver of the myeloid expansion in MPN. The contribution of increased TGF-β signaling in hematopoietic cells or other bone marrow stromal cell populations to the MPN phenotype is under investigation. Disclosures No relevant conflicts of interest to declare.
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Follenzi, Antonia, Sanj Raut, Simone Merlin, Rita Sarkar, and Sanjeev Gupta. "Role of bone marrow transplantation for correcting hemophilia A in mice." Blood 119, no. 23 (June 7, 2012): 5532–42. http://dx.doi.org/10.1182/blood-2011-07-367680.
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Abstract To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A.
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Stölzel, Friedrich, David M. Poitz, Laleh S. Arabanian, Jens Friedrichs, Denitsa Docheva, Matthias Schieker, Fernando A. Fierro, et al. "Regulation of β1-Integrin by Mir-134 in Mesenchymal Stromal Cells – Implications for Mesenchymal Stromal Cell Adherence and Hematopoietic Stem Cell Interaction." Blood 120, no. 21 (November 16, 2012): 3459. http://dx.doi.org/10.1182/blood.v120.21.3459.3459.
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Abstract Abstract 3459 The different intra- and extracellular constituents of the hematopoietic stem cell (HSC) niche in the human bone marrow are tightly regulated and of momentous importance for various properties of HSCs. Some of these are regulated through β1-Integrins (CD29) which therefore dramatically influence HSC and mesenchymal stromal cell (MSC) interaction in the niche. Important regulators within these cells are microRNAs (miRNAs). These small, non-coding RNAs control the expression of around two-thirds of the human protein-coding genes. One of these miRNAs, miR-134, previously referred to be a “brain-specific” miRNA was shown to be highly expressed in MSCs in tissue-studies conducted by our group. Since the central nervous system was recently shown to be closely connected to the regulation of HSCs and MSCs, we asked whether miR-134 which has several conserved binding seed-match sequences within the 3'UTR of β1-Integrin, regulates MSC mediated properties in the bone marrow niche. Screening of human MSC cell lines (n=4) by western blotting revealed highest β1-Integrin expression in SCP-1 cells. Transfection of SCP-1 with either siRNA directed against β1-Integrin (siCD29) or pre-miRNA-134 (pre134) revealed a downregulation of β1-Integrin at the mRNA level only in siRNA transfected cells, p=0.01. In contrast, at the protein level, as measured by western blot and FACS analysis, p=0.002, β1-Integrin was downregulated by siCD29 as well as by pre134, indicating a miRNA-specific action of repression. Confirmatory, the 3'UTR of β1-Integrin, which contains several putative binding sites for miR-134, was cloned into a pMiRReporter vector and luciferase activity was measured after cotransfection with pre134. The luciferase activity was significantly reduced in pre134 transfected cells [1.80 ± 0.46 (preCo) vs. 0.99 ± 0.49 (pre134); p<0.001]. To evaluate whether pre134 mediated reduction of β1-Integrin can modulate the adhesion potential of SCP-1, atomic force microscopy (AFM)-based single-cell force spectroscopy (SCFS) was performed. Indeed, transfection of SCP-1 with siCD29 or pre134 resulted in a significantly reduced adherence as compared to their respective controls, p<0.001 and p<0.01. Furthermore, using AFM-based SCFS we investigated the interaction between 32D-cells, which have a high surface expression of the natural interaction partner of β1-Integrin VCAM-1, and SCP-1 cells. Here again, we were able to show, that 32D show a significantly lower adhesion potential to siCD29 and pre134-transfected SCP-1, p<0.001 and p<0.001, respectively. In a translational approach MSCs from healthy bone marrow donors (n=30) and from MDS patients (n=17) were screened for miRNA-expression. This analysis revealed 50% higher miR-134 transcript levels in MSCs from MDS patients [0.0057 ± 0.0021 (healthy) vs. 0.0127 ± 0.0045 (MDS); p<0.001], suggesting a potential role of this miRNA in regulating its MSC adhesion. Regulation of adhesion of MSCs and to MSCs is important for various components of the bone marrow niche. Here, we demonstrate for the first time that β1-Integrin mediated adhesion of MSCs themselves and other cell types onto MSCs via β1-Integrin receptors can be inhibited via miR-134 overexpression. Furthermore, this newly characterized mechanism provides evidence for a potential anti-adhesive influence of miR-134. While this might not only influence adhesion, other mechanisms such as homing of HSCs as well as other cell types, might be affected by modification of miR-134 expression in the stromal niche. Disclosures: Platzbecker: Amgen: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy.
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Mangolini, Maurizio, and Ingo Ringshausen. "Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies." International Journal of Molecular Sciences 21, no. 4 (February 21, 2020): 1466. http://dx.doi.org/10.3390/ijms21041466.
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All B cell leukaemias and a substantial fraction of lymphomas display a natural niche residency in the bone marrow. While the bone marrow compartment may only be one of several sites of disease manifestations, the strong clinical significance of minimal residual disease (MRD) in the bone marrow strongly suggests that privileged niches exist in this anatomical site favouring central elements of malignant transformation. Here, the co-existence of two hierarchical systems, originating from haematopoietic and mesenchymal stem cells, has extensively been characterised with regard to regulation of the former (blood production) by the latter. How these two systems cooperate under pathological conditions is far less understood and is the focus of many current investigations. More recent single-cell sequencing techniques have now identified an unappreciated cellular heterogeneity of the bone marrow microenvironment. How each of these cell subtypes interact with each other and regulate normal and malignant haematopoiesis remains to be investigated. Here we review the evidences of how bone marrow stroma cells and malignant B cells reciprocally interact. Evidently from published data, these cell–cell interactions induce profound changes in signalling, gene expression and metabolic adaptations. While the past research has largely focussed on understanding changes imposed by stroma- on tumour cells, it is now clear that tumour-cell contact also has fundamental ramifications for the biology of stroma cells. Their careful characterisations are not only interesting from a scientific biological viewpoint but also relevant to clinical practice: Since tumour cells heavily depend on stroma cells for cell survival, proliferation and dissemination, interference with bone marrow stroma–tumour interactions bear therapeutic potential. The molecular characterisation of tumour–stroma interactions can identify new vulnerabilities, which could be therapeutically exploited.
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Khatri, Mahesh, and Yehia M. Saif. "Influenza virus Infects Bone Marrow Mesenchymal Stromal Cells in Vitro: Implications for Bone Marrow Transplantation." Cell Transplantation 22, no. 3 (March 2013): 461–68. http://dx.doi.org/10.3727/096368912x656063.
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Strub, M., L. Keller, Y. Idoux-Gillet, H. Lesot, F. Clauss, N. Benkirane-Jessel, and S. Kuchler-Bopp. "Bone Marrow Stromal Cells Promote Innervation of Bioengineered Teeth." Journal of Dental Research 97, no. 10 (June 7, 2018): 1152–59. http://dx.doi.org/10.1177/0022034518779077.
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Transplantation of bone marrow mesenchymal stem cells (BMDCs) into a denervated side of the spinal cord was reported to be a useful option for axonal regeneration. The innervation of teeth is essential for their function and protection but does not occur spontaneously after injury. Cultured reassociations between dissociated embryonic dental mesenchymal and epithelial cells and implantation lead to a vascularized tooth organ regeneration. However, when reassociations were coimplanted with a trigeminal ganglion (TG), innervation did not occur. On the other hand, reassociations between mixed embryonic dental mesenchymal cells and bone marrow–derived cells isolated from green fluorescent protein (GFP) transgenic mice (BMDCs-GFP) (50/50) with an intact and competent dental epithelium (ED14) were innervated. In the present study, we verified the stemness of isolated BMDCs, confirmed their potential role in the innervation of bioengineered teeth, and analyzed the mechanisms by which this innervation can occur. For that purpose, reassociations between mixed embryonic dental mesenchymal cells and BMDCs-GFP with an intact and competent dental epithelium were cultured and coimplanted subcutaneously with a TG for 2 wk in ICR mice. Axons entered the dental pulp and reached the odontoblast layer. BMDCs-GFP were detected at the base of the tooth, with some being present in the pulp associated with the axons. Thus, while having a very limited contribution in tooth formation, they promoted the innervation of the bioengineered teeth. Using quantitative reverse transcription polymerase chain reaction and immunostainings, BMDCs were shown to promote innervation by 2 mechanisms: 1) via immunomodulation by reducing the number of T lymphocytes (CD3+, CD25+) in the implants and 2) by expressing neurotrophic factors such as NGF, BDNF, and NT3 for axonal growth. This strategy using autologous mesenchymal cells coming from bone marrow could be used to innervate bioengineered teeth without treatment with an immunosuppressor such as cyclosporine A (CsA), thus avoiding multiple side effects.
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Borella, Giulia, Giorgia Longo, Ambra Da Ros, Elisabetta Campodoni, Margherita Montanari, Maddalena Benetton, Salvatore Nicola Bertuccio, et al. "Mesenchymal Stromal Cell Secretome in Acute Myeloid Leukemia Bone Marrow Niche." Blood 140, Supplement 1 (November 15, 2022): 8627–28. http://dx.doi.org/10.1182/blood-2022-167039.
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Ye, Jie yu, En yu Liang, Su yi Li, Godfrey ChiFung Chan, and Mo Yang. "Serotonin regulates TPO production from bone marrow mesenchymal stromal cells." Blood 122, no. 21 (November 15, 2013): 3690. http://dx.doi.org/10.1182/blood.v122.21.3690.3690.
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Abstract The bone marrow (BM) microenvironment plays an important role in regulation of thrombopoiesis through release of thrombopoietic growth factor, among which thrombopoietin (TPO) is the most essential regulator. It has been realized that the TPO blood level and platelet count is inversely related, but the precise controlling mechanism is still under investigation. TPO is constitutively produced by the liver but can be induced to generate from BM mesenchymal stromal cells (MSCs) in pathological conditions such as thrombocytopenia. Since serotonin (5-HT) can be released from the active platelets when the body undergoing severe thrombocytopenia or stress, it may function as an essential humoral mediator regulating TPO production under this model. Our previous studies suggested that 5-HT enhances the growth of the colony-forming unit-fibroblast (CFU-F), a progenitor of MSCs (Yang M et al, 2007). However, the exact functions of 5-HT on MSCs and especially MSCs-derived TPO production are still under investigated. In this study, we showed that TPO RNA expression in hMSCs was enhanced in a time-dependent manner in response to the 5-HT treatment (200nM). The maximum reaction peak was observed at 24 hrs with 1.5-fold increase compared to the untreated control. A significant increase TPO protein was found in the supernatants secreted by 5-HT-treated hMSCs. The changes measured by ELISA and cytokinearray and were 4.5-fold (P=0.0372, n=4) and 2.14-fold increased compared to the control sample. Microparticles (MPs) are membrane-derived particles (0.1-1.0μm in size) produced from activated or apoptotic cells. They have been described as an important mediator in regulating a wide range of physiological and pathological response by transforming a spectrum of cytokines, signaling proteins, mRNAs and microRNAs. Recent studies have suggested that BM MSCs is one of the major sources for MPs production and that RNA contained in MSC-derived MPs can be isolated. Therefore, TPO mRNA released from MSCs could also be stored in MPs and released into the circulation or functions in a paracrine manner. In this study, in addition to the evaluation of the effect of 5-HT on naked-TPO release from MSCs, we also investigate its impacts on the RNA expression of TPO contained within the MSC-derived MPs. 5-HT was added to the hMSC culture for 24hrs, 36hrs and 48hrs respectively. It significantly stimulated MPs released from MSCs detected by flow cytometry. The maximal response time was observed at 36hrs. The AnnexinV positive population increased remarkably under 5-HT treatment (P=0.0007, n=4). HtMSC Cell movement and MPs released were visualized under phase contrast microscopy. HtMSC cells with 5-HT treatment were stained with AnnexinV-PE and the plates were inspected under the Tirf microscopy to trace the shedding process of MPs. By using phase contrast microscopy, a notable generation of MPs was observed from approximate 6hrs after the addition of 5HT, while only a little amount of MPs were detected in the untreated control group. Budding MPs were observed in 5HT-treated MSCs under both SEM and TEM. The morphology of these MPs was compatible to those published in other studies. And these results were complementary to our previous data obtained by flow cytometry and Tirf microscopy. Our data proved that hMSCs-derived MPs contained inducible TPO mRNA, which was enhanced under 5-HT treatment with more than 10-fold increase compared to the untreated control (P=0.0025, n=3). We further examined protein level of TPO in MPs using ELISA. The TPO protein level was increased more than 3-fold in 5-HT treated sample (P=0.0052, n=3). In summary, our findings suggested that 5-HT stimulated TPO released from MSCs in both dissociative and MP-bounded form, which indirectly promotes megakaryopoiesis and thrombopoiesis. Disclosures: No relevant conflicts of interest to declare.
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Nemeth, Michael, and David Bodine. "β-Catenin Expression in Cultured Bone Marrow Stromal Cells Is Required To Maintain Production of Osteoblasts and Hematopoietic Progenitor Cells." Blood 108, no. 11 (November 16, 2006): 85. http://dx.doi.org/10.1182/blood.v108.11.85.85.
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Abstract The canonical Wnt signaling pathway is defined by Wnt ligand-mediated stabilization and nuclear translocation of β-catenin to induce target gene expression. This pathway has been demonstrated to regulate differentiation of mesenchymal tissue, which includes the cell types (e.g. osteoblasts, myofibroblasts, adipocytes) that comprise the stromal cells of the hematopoietic microenvironment. We hypothesized that loss of canonical Wnt signaling would result in disruption of the ability of stromal cells to support hematopoiesis. To test this hypothesis, we generated transgenic mice that expressed conditonal loss of function β-catenin alleles along with Cre-recombinase under the control of the inducible Mx1 promoter, which is active in bone marrow. We induced excision of β-catenin by injecting β-cateninlox/lox Mx-cre+/cre mice with 10 doses of 300 mg/ml pIpC. Whole bone marrow from treated (KO) and untreated (WT) animals was used to establish Dexter stromal cultures with an input of 1 × 106 cells/cm2 culture surface area. PCR performed on DNA isolated from KO stromal cells showed that nearly 100% deletion of β-catenin occurred with this regimen. To determine the ability of KO stroma to support hematopoiesis, irradiated KO and WT stromal cultures were seeded with 4 × 104 normal lin− cells/cm2. There were no differences in cell expansion, cell cycle activity, or apoptosis between hematopoietic cells cultured on WT vs. KO stroma. We determined the capacity of β-catenin deficient stroma to maintain hematopoietic progenitors by measuring myeloid CFU formation after 1, 2, and 3 weeks in culture. After 1 week, hematopoietic cells cultured on WT stroma contained 5-fold more CFU-GM (151.7 ± 21.4 CFU-GM/1×104 cells) than cells cultured on KO stroma (28.7 ± 4.9; n = 6, p < .001). Similar differences in CFU-GM formation were observed after 2 weeks (WT 46.5 ± 8.0 vs. KO 10.3 ± 1.7; n = 6, p< .001) and 3 weeks (WT 16.5 ± 2.8 vs. KO 2.6 ± 1.5; n = 6, p < .001) in culture. This decrease in the production of hematopoietic progenitor cells was not due to decreased numbers of stromal cells as the average number of KO stromal cells (4.8 ± 0.07 × 104/cm2) was greater than WT (3.7 ± 0.7 × 104/cm2; n = 3, p = .05). We also determined the ability of WT and KO mesenchymal progenitors to generate fibroblast colonies (CFU-F) and found no difference between WT (17 ± 1.8 CFU-F/1 × 106 bone marrow cells) and KO (15.8 ± 3.5; n = 4, p = .54). Canonical Wnt signaling has been proposed to regulate the differentiation of mesenchymal stem cells into osteoblasts. Since osteoblasts contribute to the proper regulation of hematopoiesis, we hypothesized that the depletion of hematopoietic progentiors in KO stromal cultures is due to a reduction in the number of osteoblasts. To detect osteoblasts in vitro, we performed histochemical staining to detect alkaline phosphatase (ALP) activity in WT and KO stromal cultures and scored the positive cells. We observed a significant 50% reduction in the percentage of ALP+ cells in KO stroma (13.2 ± 4.8%) compared to WT (28.0 ± 7.9%) (n = 3, p = .05). In summary, these data indicate that loss of canonical Wnt signaling results in decreased support of hematopoietic progenitors and osteoblasts. From these data, we propose a model in which canonical Wnt signaling is necessary to maintain normal numbers of osteoblasts within the bone marrow stroma and that loss of β-catenin leads to a decrease in the number of osteoblasts and a subsequent reduction in the ability of the stroma to support hematopoiesis.