scholarly journals Mast Cell-Activated Bone Marrow Mesenchymal Stromal Cells Regulate Proliferation and Lineage Commitment of CD34+ Progenitor Cells

2013 ◽  
Vol 4 ◽  
Author(s):  
Zoulfia Allakhverdi ◽  
Michael R. Comeau ◽  
Myriam Armant ◽  
Rachana Agrawal ◽  
Judith A. Woodfolk ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Lineage Commitment

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.

scholarly journals The spatiotemporal expression patterns of MSC-associated markers contribute to the identification of progenitor subpopulations in developing limbs

2020 ◽  
Vol 64 (10-11-12) ◽  
pp. 499-506
Author(s):  
Argelia S. García-Cervera ◽  
Jesús Chimal-Monroy ◽  
Jessica C. Marín-llera
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Limb Development ◽  
Expression Patterns ◽  
Spatiotemporal Expression ◽  
Undifferentiated Cells ◽  
Adult Mscs

During limb development, skeletal tissues differentiate from their progenitor cells in an orchestrated manner. Mesenchymal stromal cells (MSCs), which are considered to be adult undifferentiated/progenitor cells, have traditionally been identified by the expression of MSC-associated markers (MSC-am) and their differentiation capacities. However, although MSCs have been isolated from bone marrow and a variety of adult tissues, their developmental origin is poorly understood. Remarkably, adult MSCs share similar differentiation characteristics with limb progenitors. Here, we determined the expression patterns of common MSC-am throughout mouse hindlimb development. Our results demonstrate that MSC-am expression is not restricted to undifferentiated cells in vivo. Results from the analysis of MSC-am spatiotemporal expression in the embryonic hindlimb allowed us to propose five subpopulations which represent all limb tissues that potentially correspond to progenitor cells for each lineage. This work contributes to the understanding of MSC-am expression dynamics throughout development and underlines the importance of considering their expression patterns in future MSC studies of the limb.

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.

In Vitro Effect of Neopterin on Splenic Mast Cell Development in Senescence Accelerated Mice (SAM)

Pteridines ◽  
2007 ◽  
Vol 18 (1) ◽  
pp. 101-105
Author(s):  
Tomonori Harada ◽  
Isao Tsuboi ◽  
Miyuki Yuda ◽  
Kazunori Wakasugi ◽  
Shin Aizawa
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Culture System ◽  
Inflammatory Responses ◽  
Spleen Cells ◽  
Mast Cell Progenitor ◽  
Vitro Effect

Abstract Neopterin is produced by monocytes and is a useful biomarker of inflammatory responses. We found that neopterin enhances granulopoiesis, but suppresses B-lymphopoiesis triggered by the positive- and negative regulations of cytokines produced by stromal cells in mice. Furthermore, neopterin suppressed the colony formation of mast cell progenitor (CFU-mast) from bone marrow cells in in vitro culture system. In this study, neopterin was also found to regulate the proliferation and differentiation of splenic CFU-mast in vitro as observed in that from bone marrow, which was confirmed in the mouse model of senescent stromal-cell impairment (SCI). In non- SCI mice (=less senescent stage of SCI mice), neopterin also decreased the number of colonies of interleukin-3 (IL-3)-dependent mast-cell progenitor cells (CFU-mast) from unfractionated spleen cells, but not that from the lineage-negative (fractionated) spleen cell population without stromal cells in a semisolid in vitro culture system. In contrast, in a case of SCI mice, the treatment with neopterin did not decrease the number of colonies of IL-3- dependent mast-cell progenitor cells (CFU-mast) from unfractionated spleen cells. These results suggest that, firstly, neopterin decrease the number of colonies of IL-3-dependent CFU-mast by stimulating splenic stromal cells, and secondly, such neopterin function becomes declined during senescence because of an impaired stromalcell function.

scholarly journals Nanotopography Induced Human Bone Marrow Mesangiogenic Progenitor Cells (MPCs) to Mesenchymal Stromal Cells (MSCs) Transition

2016 ◽  
Vol 4 ◽  
Author(s):  
Sara Antonini ◽  
Marina Montali ◽  
Emanuela Jacchetti ◽  
Sandro Meucci ◽  
Paolo D. Parchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Human Bone ◽  
Human Bone Marrow
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