Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis

2020 ◽  
Vol 100 (1) ◽  
pp. 105-116
Author(s):  
Benedetta Rambaldi ◽  
Elisa Diral ◽  
Samantha Donsante ◽  
Noemi Di Marzo ◽  
Federica Mottadelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Niche ◽  
Marrow Fibrosis

scholarly journals TGF-β Signaling in Stromal Cells Contributes to Myelofibrosis, but Not Niche Disruption, in Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1463-1463
Author(s):  
Juo-Chin Yao ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloproliferative Neoplasms ◽  
Extramedullary Hematopoiesis ◽  
Bone Marrow Niche ◽  
Kit Ligand ◽  
Ligand Expression ◽  
The Impact ◽  
Hematopoietic Niche

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.

scholarly journals Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 68
Author(s):  
Fulvio Massaro ◽  
Florent Corrillon ◽  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Laurence Lagneaux ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Communication ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

scholarly journals TGF-Beta Signaling in Mesenchymal Stromal Cells Contributes to Myelofibrosis but Not Hematopoietic Phenotypes in Myeloproliferative Neoplasms

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3053-3053
Author(s):  
Juo-Chin Yao ◽  
Grazia Abou Ezzi ◽  
Joseph R. Krambs ◽  
Eric J. Duncavage ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Hematopoietic Cells ◽  
Dismal Prognosis ◽  
Collagen Iii

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.

scholarly journals Gli1+ Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target

2018 ◽  
Vol 23 (2) ◽  
pp. 308-309 ◽  
Author(s):  
Rebekka K. Schneider ◽  
Ann Mullally ◽  
Aurelien Dugourd ◽  
Fabian Peisker ◽  
Remco Hoogenboezem ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Target ◽  
Bone Marrow Fibrosis ◽  
Key Driver ◽  
Marrow Fibrosis

scholarly journals EBF1 As a Novel Regulator of Bone Marrow Mesenchymal Stromal Progenitors

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 96-96
Author(s):  
Marta Derecka ◽  
Senthilkumar Ramamoorthy ◽  
Pierre Cauchy ◽  
Josip Herman ◽  
Dominic Grun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloid Cells ◽  
Bone Marrow Niche ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Abstract Hematopoietic stem and progenitor cells (HSPC) are in daily demand worldwide because of their ability to replenish entire blood system. However, the in vitro expansion of HSPC is still a major challenge since the cues from bone marrow microenvironment remain largely elusive. Signals coming from the bone marrow niche, and specifically mesenchymal stem and progenitor cells (MSPC), orchestrate maintenance, trafficking and stage specific differentiation of HSPCs. Although, it is generally accepted that MSPCs are essential for hematopoietic homeostasis and generating multiple types of stromal cells, the exact transcriptional networks regulating MSPCs are not well established. Early B-cell factor 1 (Ebf1) has been discovered as lineage-specific transcription factor governing B lymphopoiesis. Additionally, it has been shown to play important role in differentiation of adipocytes, which are a niche component supporting hematopoietic regeneration. Thus, in this study we seek to examine if Ebf1 has an alternative function in non-hematopoietic compartment of bone marrow, specifically in mesenchymal stromal cells that maintain proper hematopoiesis. Here, we identified Ebf1 as new transcription regulator of MSPCs activity. Mesenchymal progenitors isolated from Ebf1-/- mice show diminished capacity to form fibroblasticcolonies (CFU-F) indicating reduced self-renewal. Moreover, cells expanded from these colonies display impaired in vitro differentiation towards osteoblasts, chondrocytes and adipocytes. In order to test how this defective MSPCs influence maintenance of HSPCs, we performed long-term culture-initiating cell assay (LTC-IC). After 5 weeks of co-culture of Ebf1-deficient stromal cells with wild type HSPCs we could observe significantly decreased number of cobblestone and CFU colonies formed by primitive HSPCs, in comparison to co-cultures with control stromal cells. Furthermore, in vivo adoptive transfers of wild type HSPCs to Ebf1+/- recipient mice showed a decrease in the absolute numbers of HSPCs in primary recipients and reduced donor chimerism within the HSCP compartment in competitive secondary transplant experiments. Additionally, Prx1-Cre-mediated deletion of Ebf1 specifically in MSPCs of mice leads to reduced frequency and numbers of HSPCs and myeloid cells in the bone marrow. These results confirm that mesenchymal stromal cells lacking Ebf1 render insufficient support for HSPCs to sustain proper hematopoiesis. Interestingly, we also observed a reduced ability of HSPCs sorted from Prx1CreEbf1fl/fl mice to form colonies in methylcellulose, suggesting not only impaired maintenance but also hindered function of these cells. Moreover, HSPCs exposed to Ebf1-deficient niche exhibit changes in chromatin accessibility with reduced occupancy of AP-1, ETS, Runx and IRF motifs, which is consistent with decreased myeloid output seen in Prx1CreEbf1fl/fl mice. These results support the hypothesis that defective niche can cause epigenetic reprograming of HSPCs. Finally, single cell and bulk transcriptome analysis of MSPCs lacking Ebf1 revealed differences in the niche composition and decreased expression of lineage-instructive signals for myeloid cells. Thus, our study establishes Ebf1 as a novel regulator of MSPCs playing a crucial role in the maintenance and differentiation of HSPCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of Amino Acids in the Crosstalk Between Mesenchymal Stromal Cells and Neoplastic Cells in the Hematopoietic Niche

2021 ◽  
Vol 9 ◽  
Author(s):  
Martina Chiu ◽  
Giuseppe Taurino ◽  
Massimiliano G. Bianchi ◽  
Ovidio Bussolati
Keyword(s):  
Amino Acids ◽  
Bone Marrow ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Immune Cells ◽  
Stromal Cells ◽  
Bone Marrow Niche ◽  
Differentiation Potential

Within the bone marrow hematopoietic cells are in close connection with mesenchymal stromal cells (MSCs), which influence the behavior and differentiation of normal or malignant lymphoid and myeloid cells. Altered cell metabolism is a hallmark of cancer, and changes in nutrient pools and fluxes are important components of the bidirectional communication between MSCs and hematological cancer cells. Among nutrients, amino acids play a significant role in cancer progression and chemo-resistance. Moreover, selected types of cancer cells are extremely greedy for glutamine, and significantly deplete the extracellular pool of the amino acid. As a consequence, this influences the behavior of MSCs in terms of either cytokine/chemokine secretion or differentiation potential. Additionally, a direct nutritional interaction exists between MSCs and immune cells. In particular, selected subpopulations of lymphocytes are dependent upon selected amino acids, such as arginine and tryptophan, for full differentiation and competence. This review describes and discusses the nutritional interactions existing in the neoplastic bone marrow niche between MSCs and other cell types, with a particular emphasis on cancer cells and immune cells. These relationships are discussed in the perspective of potential novel therapeutic strategies based on the interference on amino acid metabolism or intercellular fluxes.

scholarly journals Single Cell Transcriptomic Analysis of the Multiple Myeloma Bone Marrow Identifies a Unique Inflammatory Stromal Cell Population Associated with TNF Signaling

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 690-690
Author(s):  
Madelon M.E. de Jong ◽  
Zoltan Kellermayer ◽  
Natalie Papazian ◽  
M Duin ◽  
Annemiek Broyl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Single Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Research Funding ◽  
Stromal Cell ◽  
Gene Set Enrichment Analysis ◽  
Bone Marrow Niche ◽  
Cell Clusters

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.

scholarly journals Alteration of the Hematopoietic Components, Mesenchymal Stromal Cells and Vascular Elements in the Bone Marrow Niche in Myelodysplastic Syndrome: Refractory Cytopenia with Multilineage Dysplasia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5516-5516
Author(s):  
Salar Abbas ◽  
Aparna Venkatraman ◽  
Sanjay Kumar ◽  
Archana Kini ◽  
Marie Therese Manipadam ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Conflicts Of Interest ◽  
Proliferation Index ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Multilineage Dysplasia ◽  
Vascular Elements

Abstract Introduction:The myelodysplastic syndromes (MDS) are clonal disorders characterized by cytopenias and abnormal hematopoiesis. Though there are reports of perturbations in the hematopoietic stem cells (HSC) and the mesenchymal stromal cells (MSC) as well as other elements of the bone marrow (BM) niche in an instructive or permissive manner leading to the genesis of ineffective hematopoiesis in this condition, most studies have evaluated single elements. Here we demonstrate altered HSC, MSC and the vascular niche elements in patients with MDS - Refractory cytopenia with multilineage dysplasia (RCMD). Methods and results: Bone marrow aspirates from patients with RCMD (n=12, mean age 54.33±14.51 years) were compared with those from age-matched controls (n=18, mean age 47.78±18.60 years) who had a 'normal' marrow obtained for other diagnostic purposes. Cytogenetic analysis showed abnormal karyotypes in seven patients and normal karyotypes in five. The abnormalities seen were as follows: deletion 7q/monosomy 7 (four patients), deletion 5q (three patients), loss of Y (two patients), monosomy 5, deletion 20q (one each), complex karyotypes (four patients). Phenotypic enumeration of HSPCs revealed a marked decrease in the frequency of highly purified HSCs (Lin-CD34+CD38-CD90+CD45RA-) in RCMD (0.04135±0.01748%, n=11) when compared to controls (0.3168±0.05266%, n=13, p<0.0001) (Figure 1). Patients with RCMD also had increased common myeloid progenitors (CMP) (3.221 ± 0.7478%, n=8) compared to control (1.243±0.4463%, n=10, p<0.0302) and loss of granulocyte-macrophage progenitors (GMP) (0.4863±0.1638%, n=8) compared to controls (2.047±0.5422%, n=10, p<0.0242) (Figure 2). Assessment of the frequency of de novo MSCs (CD31-CD45/CD71- population) expressing CD271 and/or CD146, indicating the more primitive population, in total nucleated cells showed increased CD271+CD146-MSCs (0.632±0.2, n=5) compared to controls (0.2000±0.05158, n=6, p<0.0401) as also the CD271+CD146+ MSCs (0.2900±0.09803, n=5) in RCMD patients when compared to controls (0.02861±0.01354, n=6, p<0.0172) (Figure 3). We also evaluated in vitro cultured MSCs (P4) in these patients. CD271+CD146+ MSCs within total cultured MSCs were higher (0.1900±0.06429%, n=3) than in controls (0.0040±0.0040%, n=3, p<0.0447). RCMD MSCs had significantly lower proliferation index (32±3.7%, n=3) compared to controls (60±9.2%, n=3, p<0.0479). Cell cycle analysis of MSC showed significantly lower numbers in G0 in RCMD (0.1567 ± 0.07881 %, n=3) compared to control (0.6400 ± 0.1007 %, n=3; p<0.0194). Apoptosis was much higher in RCMD MSCs (2.700±0.8007%, n=3) compared to controls (0.03633±0.01802%, n=3, P<0.0292). No significant differences in expression profile of stem cell maintenance related cytokines and growth factors (CXCL12a, SCF, VEGF, ANGPT and LIF ) or components of Notch (Notch1, Notch3, Jagged-1, Delta like-1 and Hes1) and Wnt (Dkk1 and Dkk-2) pathways were found between RCMD and control MSCs within the limited numbers evaluated. Interestingly, unlike controls, immunofluorescence imaging of bone marrow trephine from MDS-RCMD revealed CD271+CD146+ MSCs co-localized with sinusoids and in direct contact with CD34+ (<5% blast) HSC/progenitor cells (HSPCs). Conclusion: Our data shows that in patients with MDS-RCMD, both qualitative and quantitative abnormalities exist in the HSC, HSPC and niche elements. We also show that the cytopenia could be related to decreased numbers of primitive HSCs and a differentiation arrest at the CMP stage. Primitive MSCs are reduced, and those that exist show poorer proliferative and survival features. Further studies are needed to understand the cause and effect relationship of these changes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Kevin Woods ◽  
Borhane Guezguez
Keyword(s):  
Bone Marrow ◽  
Cell Population ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
The Body ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Functional Immunity

Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism’s lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called “niche” that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

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