TGF-β Signaling Plays an Essential Role in the Lineage Specification of Mesenchymal Stem/Progenitor Cells in Fetal Bone Marrow

Abstract

Summary: Mesenchymal 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. : Link and colleagues show the pivotal role of TGF-β signaling in mesenchymal cells on the emergence of hematopoietic niches in the bone marrow during fetal development. Abrogating TGF-β signaling in mesenchymal cells during development results in a marked expansion of adipocytes and CAR cells in the bone marrow, while osteoblasts are reduced. Keywords: mesenchymal stem cells, transforming growth factor β, bone marrow niche, lineage commitment, hematopoiesis, bone metabolism, adipocyte, CAR cells, and osteoblast