Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States of America.
PLoS One. 2020 May 29;15(5):e0233751. doi: 10.1371/journal.pone.0233751. eCollection 2020.
Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress erythropoiesis responses to acute hemolytic anemia were normal. TGF-β potently inhibits stromal CXCL12 expression in vitro; however, G-CSF induced decreases in bone marrow CXCL12 expression and subsequent hematopoietic stem/progenitor cell mobilization were normal in Osx-Cre, Tgfbr2fl/fl mice, in which all TGF-β signaling in mesenchymal stromal is lost. Finally, although a prior study showed that TGF-β enhances recovery from myeloablative therapy, hematopoietic recovery following single or multiple doses of 5-flurauracil were normal in Osx-Cre, Tgfbr2fl/fl mice. Collectively, these data suggest that TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions.
间质基质细胞是骨髓造血龛的重要组成部分。先前的研究表明，间质基质细胞中转化生长因子（TGF）超家族成员的信号对于正常龛的发育是必需的。在这里，我们通过在出生时删除间质基质细胞中的 Smad4 来评估 TGF 家族信号对龛维持和应激反应的影响，从而消除了经典的 TGF 信号。在 Osx-Cre、Smad4fl/fl 小鼠中，未观察到 CXCL12 丰富的网状（CAR）细胞、成骨细胞或脂肪细胞的数量或空间组织发生改变，关键龛因子的表达正常。基础造血和急性溶血性贫血应激性红细胞生成反应正常。TGF-β 在体外强烈抑制基质 CXCL12 的表达；然而，在 Osx-Cre、Tgfbr2fl/fl 小鼠中，G-CSF 诱导的骨髓 CXCL12 表达降低以及随后的造血干细胞/祖细胞动员正常，其中所有 TGF-β 信号在间质基质中均丧失。最后，尽管先前的一项研究表明 TGF-β 增强了骨髓清除疗法的恢复，但在 Osx-Cre、Tgfbr2fl/fl 小鼠中，单次或多次 5-氟尿嘧啶给药后的造血恢复正常。总的来说，这些数据表明，间质基质细胞中 TGF 家族成员信号在基础和应激条件下对造血龛的维持是可有可无的。
