Abstract
SummaryMesenchymal stromal cells are key components of hematopoietic niches in the bone marrow. Here we abrogated transforming growth factor β (TGF-β) signaling in mesenchymal stem/progenitor cells (MSPCs) by deleting Tgfbr2 in mesenchymal cells using a doxycycline-repressible Sp7 (osterix)-Cre transgene. We show that loss of TGF-β signaling during fetal development results in a marked expansion of CXCL12-abundant reticular (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-β signaling is dispensable for the maintenance of mesenchymal cells in the bone marrow after birth under steady-state conditions. Collectively, these data show that TGF-β plays 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.
Highlights
The bone marrow microenvironment is uniquely adapted to support hematopoiesis
We show that loss of transforming growth factor b (TGF-b) signaling in Osx-Cretargeted fetal mesenchymal stem/progenitor cells (MSPCs) results in alterations in mesenchymal stromal cells, including marked expansions of CXCL12-abundant reticular (CAR) cells and adipocytes
Deletion of Tgfbr2 in Osx-Cre-Targeted Mesenchymal Cells Results in a Loss of Mature Osteoblasts To investigate the role of TGF-b in the development and maintenance of bone marrow mesenchymal stromal cells, we deleted Tgfbr2 in mesenchymal cells using a doxycycline-repressible Sp7-Cre transgene (Osx-Cre) (Maes et al, 2010)
Summary
The bone marrow microenvironment is uniquely adapted to support hematopoiesis. A complex network of stromal cells in the bone marrow provides key signals that support the proliferation and survival of hematopoietic stem/ progenitor cells (Calvi and Link, 2015). Adipocytes are rare in the bone marrow at birth but increase with aging and after myeloablation (Justesen et al, 2001; Zhou et al, 2017). The presence of adipocytes in the bone marrow negatively correlates with hematopoietic activity (Naveiras et al, 2009). A recent study showed that adipocytes promote hematopoietic recovery following myeloablation through production of stem cell factor (Zhou et al, 2017), suggesting a context-specific role for adipocytes in regulating hematopoiesis
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