Overexpression of Jagged-1 and Its Intracellular Domain in Human Mesenchymal Stromal Cells Differentially Affect the Interaction with Hematopoietic Stem and Progenitor Cells

2013 ◽  
Vol 22 (20) ◽  
pp. 2736-2750 ◽  
Author(s):  
Regina Duryagina ◽  
Sebastian Thieme ◽  
Konstantinos Anastassiadis ◽  
Carsten Werner ◽  
Susan Schneider ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Intracellular Domain ◽  
Hematopoietic Stem ◽  
Human Mesenchymal Stromal Cells ◽  
Stem And Progenitor Cells

scholarly journals Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells' homeostasis

Oncotarget ◽  
2016 ◽  
Vol 7 (12) ◽  
pp. 13285-13296 ◽  
Author(s):  
Kelsey O’Hagan-Wong ◽  
Stéphanie Nadeau ◽  
Audrey Carrier-Leclerc ◽  
Felipe Apablaza ◽  
Reggie Hamdy ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Hematopoietic Stem ◽  
Human Mesenchymal Stromal Cells ◽  
Stem And Progenitor Cells

scholarly journals Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes

2018 ◽  
Vol 27 (5) ◽  
pp. 754-764 ◽  
Author(s):  
Domenico Mattiucci ◽  
Giulia Maurizi ◽  
Pietro Leoni ◽  
Antonella Poloni
Keyword(s):  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Myelodysplastic Syndromes ◽  
Stromal Cells ◽  
Replicative Senescence ◽  
Special Focus ◽  
Proliferative Potential ◽  
Stromal Compartment ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Hematopoietic stem and progenitor cells reside within the bone marrow (BM) microenvironment. By a well-balanced interplay between self-renewal and differentiation, they ensure a lifelong supply of mature blood cells. Physiologically, multiple different cell types contribute to the regulation of stem and progenitor cells in the BM microenvironment by cell-extrinsic and cell-intrinsic mechanisms. During the last decades, mesenchymal stromal cells (MSCs) have been identified as one of the main cellular components of the BM microenvironment holding an indispensable role for normal hematopoiesis. During aging, MSCs diminish their functional and regenerative capacities and in some cases encounter replicative senescence, promoting inflammation and cancer progression. It is now evident that alterations in specific stromal cells that comprise the BM microenvironment can contribute to hematologic malignancies, and there is growing interest regarding the contribution of MSCs to the pathogenesis of myelodysplastic syndromes (MDSs), a clonal hematological disorder, occurring mostly in the elderly, characterized by ineffective hematopoiesis and increased tendency to acute myeloid leukemia evolution. The pathogenesis of MDS has been associated with specific genetic and epigenetic events occurring both in hematopoietic stem cells (HSCs) and in the whole BM microenvironment with an aberrant cross talk between hematopoietic elements and stromal compartment. This review highlights the role of MSCs in MDS showing functional and molecular alterations such as altered cell-cycle regulation with impaired proliferative potential, dysregulated cytokine secretion, and an abnormal gene expression profile. Here, the current knowledge of impaired functional properties of both aged MSCs and MSCs in MDS have been described with a special focus on inflammation and senescence induced changes in the BM microenvironment. Furthermore, a better understanding of aberrant BM microenvironment could improve future potential therapies.

Synergistic effects of growth factors and mesenchymal stromal cells for expansion of hematopoietic stem and progenitor cells

2011 ◽  
Vol 39 (6) ◽  
pp. 617-628 ◽  
Author(s):  
Thomas Walenda ◽  
Gudrun Bokermann ◽  
Mónica S. Ventura Ferreira ◽  
Daniela M. Piroth ◽  
Thomas Hieronymus ◽  
...  
Keyword(s):  
Growth Factors ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Synergistic Effects ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

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 Roles for integrin very late activation antigen-4 in stroma-dependent erythropoiesis

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2844-2850 ◽  
Author(s):  
N Yanai ◽  
C Sekine ◽  
H Yagita ◽  
M Obinata
Keyword(s):  
Progenitor Cells ◽  
Adhesion Molecules ◽  
Stromal Cells ◽  
Ligand Molecule ◽  
Erythroid Cells ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Erythroid Progenitor Cells ◽  
Stem And Progenitor Cells ◽  
Activation Antigen

Abstract Adhesion molecules are required for development of hematopoietic stem and progenitor cells in the respective hematopoietic microenvironments. We previously showed that development of the erythroid progenitor cells is dependent on their direct adhesion to the stroma cells established from the erythropoietic organs. In this stroma-dependent erythropoiesis, we examined the role of adhesion molecules in erythropoiesis by blocking antibodies. The development of the erythroid cells on stroma cells was inhibited by anti-very late activation antigen-4 (VLA-4 integrin) antibody, but not by anti-VLA-5 antibody, although the erythroid cells express both VLA-4 and VLA-5. Whereas high levels of expression of vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, ligands for VLA-4, were detected in the stroma cells, the adhesion and development of the erythroid progenitor cells were partly inhibited by the blocking antibody against VCAM-1. VLA-5 and fibronectin could mediate adhesion of the erythroid progenitor cells to the stromal cells, but the adhesion itself may not be sufficient for the stroma-supported erythropoiesis. The stromal cells may support erythroid development by the adhesion through a new ligand molecule(s) for VLA-4 in addition to VCAM-1, and such collaborative interaction may provide adequate signaling for the erythroid progenitor cells in the erythropoietic microenvironment.

TGF-β Signaling in Fetal Mesenchymal Progenitor Cells Plays an Essential Role in the Emergence of Bone Marrow Hematopoietic Niches

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3847-3847
Author(s):  
Grazia Abou Ezzi ◽  
Teerawit Supakorndej ◽  
Jingzhu Zhang ◽  
Joseph R. Krambs ◽  
Hamza Celik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Essential Role ◽  
Suppressive Effect ◽  
Mesenchymal Cells ◽  
Lineage Specification ◽  
Mapk Activation ◽  
Hematopoietic Stem

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.

Sign in / Sign up

Export Citation Format

Share Document