TGF-β Signaling Plays an Essential Role in the Lineage Specification of Mesenchymal Stem/Progenitor Cells in Fetal Bone Marrow
TGF-β Signaling Plays an Essential Role in the Lineage Specification of Mesenchymal Stem/Progenitor Cells in Fetal Bone Marrow
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DOI：
10.1016/j.stemcr.2019.05.017
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发表时间：
2019-07-09
影响因子：
5.9
通讯作者：
Link, Daniel C.
中科院分区：
文献类型：
--
作者：
Abou-Ezzi, Grazia;Supakorndej, Teerawit;Link, Daniel C.
间充质基质细胞是骨髓中造血生态位的重要组成部分。在这里，我们通过使用可抑制多西环素的SP7(Osterix)-Cre转基因来删除间充质细胞中的TGFBR2，从而取消了间充质干细胞/祖细胞(MSPC)中的转化生长因子-β(TGF-β)信号。我们发现，在胎儿发育过程中，转化生长因子-β信号的丢失导致骨髓中CXCL12丰富的网状细胞(CAR)和脂肪细胞显著扩张，而成骨细胞显著减少。这些间质改变与明显的造血缺陷有关，包括从淋巴系向髓系系的转变。然而，造血干细胞的功能被保留了下来。有趣的是，在稳态条件下，转化生长因子-β信号对于出生后骨髓间充质细胞的维持是必不可少的。总而言之，这些数据表明，转化生长因子-β在胎儿但不是决定性的骨髓间充质干细胞的谱系规范中起着重要的作用，并且是在胎儿和围产期骨髓中建立正常的造血生态位所必需的。
Mesenchymal stromal cells are key components of hematopoietic niches in the bone marrow. Here we abrogated transforming growth factor beta (TGF-beta) 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-beta 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-beta 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-beta 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.