Inactivation of mTORC1 Signaling in Osterix‐Expressing Cells Impairs B‐cell Differentiation
Inactivation of mTORC1 Signaling in Osterix‐Expressing Cells Impairs B‐cell Differentiation
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DOI：
10.1002/jbmr.3352
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发表时间：
2018-04
影响因子：
6.2
通讯作者：
Yongkui Wang;Min Xiao;Chen Tao;Jing Chen;Zhenyu Wang;Jun Yang;Zhenguo Chen;Zhipeng Zou;Anling Liu;D. Cai;Yu Jiang;C. Ding;Mangmang Li;X. Bai
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作者：
Yongkui Wang;Min Xiao;Chen Tao;Jing Chen;Zhenyu Wang;Jun Yang;Zhenguo Chen;Zhipeng Zou;Anling Liu;D. Cai;Yu Jiang;C. Ding;Mangmang Li;X. Bai
成骨细胞为骨髓（BM）中的B-细胞定型和成熟提供微环境生态位。成骨细胞功能的任何缺失都可能导致B淋巴细胞生成的缺陷。来自雷帕霉素复合物1（mTORC 1）的机制靶点的信号传导已被牵连在调节成骨细胞的扩增和分化中。因此，我们提出了一个假设，即成骨细胞中的mTORC 1信号在B-细胞发育中起着至关重要的作用。通过Osx-Cre定向缺失Raptor（mTORC 1特异性组分）灭活osterix表达细胞（主要是成骨细胞谱系）中的mTORC 1导致BM中总B-细胞群减少，这是由于早期B-细胞从原B细胞阶段发育到前B细胞阶段受阻。进一步的机制研究表明，这种缺陷是由于表达osterix的未成熟成骨细胞中白细胞介素-7（IL-7）表达减少，导致早期B淋巴细胞中IL-7/Stat 5信号异常，导致前B细胞和未成熟B细胞凋亡增加。体外和体内研究表明，外源性IL-7的加入部分恢复了Raptor突变小鼠BM中的B淋巴细胞生成。此外，在Raptor无效未成熟成骨细胞的条件培养基或含有抗IL-7中和抗体的培养基中培养的总BM细胞未能分化为前B细胞和未成熟B细胞，表明未成熟成骨细胞中mTORC 1的失活不能完全支持正常B细胞发育。总之，这些发现证明了mTORC 1在调节骨髓环境中的新作用，该骨髓环境通过调节IL-7表达支持B-细胞分化。© 2017美国骨与矿物质研究学会。
Osteoblasts provide a microenvironmental niche for B‐cell commitment and maturation in the bone marrow (BM). Any abnormity of osteoblasts function may result in the defect of B lymphopoiesis. Signaling from mechanistic target of rapamycin complex 1 (mTORC1) has been implicated in regulating the expansion and differentiation of osteoblasts. Thus, we raise a hypothesis that mTORC1 signaling in osteoblasts plays a vital role in B‐cell development. Inactivation of mTORC1 in osterix‐expressing cells (mainly osteoblast lineage) through Osx‐Cre‐directed deletion of Raptor (an mTORC1‐specific component) resulted in a reduction in the total B‐cell population in the BM, which was due to a block in early B‐cell development from the pro‐B to pre‐B cell stage. Further mechanistic studies revealed that this defect was the result of reduction of interleukin‐7 (IL‐7) expression in osterix‐expressing immature osteoblasts, which caused the abnormality of IL‐7/Stat5 signaling in early B lymphocytes, leading to an increased apoptosis of pre‐B plus immature B cells. In vitro and in vivo studies demonstrated that the addition of exogenous IL‐7 partially restored B lymphopoiesis in the BM of Raptor mutant mice. Furthermore, total BM cells cultured in conditioned media from Raptor null immature osteoblasts or media with anti‐IL‐7 neutralizing antibody failed to differentiate into pre‐B and immature B cells, indicating that inactivation of mTORC1 in immature osteoblast cannot fully support normal B‐cell development. Taken together, these findings demonstrate a novel role for mTORC1 in the regulation of bone marrow environments that support B‐cell differentiation via regulating IL‐7 expression. © 2017 American Society for Bone and Mineral Research.