NOTCH Signaling Is Activated through Mechanical Strain in Human Bone Marrow-Derived Mesenchymal Stromal Cells
NOTCH Signaling Is Activated through Mechanical Strain in Human Bone Marrow-Derived Mesenchymal Stromal Cells
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DOI：
10.1155/2019/5150634
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发表时间：
2019-02
影响因子：
4.3
通讯作者：
Fani Ziouti;R. Ebert;Maximilian Rummler;Melanie Krug;S. Müller-Deubert;M. Lüdemann;F. Jakob;B. Wi
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文献类型：
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作者：
Fani Ziouti;R. Ebert;Maximilian Rummler;Melanie Krug;S. Müller-Deubert;M. Lüdemann;F. Jakob;B. Wi
在转基因小鼠中，成年骨的骨骼发育和重塑受到激活的NOTCH信号的关键控制。目前还不清楚NOTCH信号是否被骨细胞感受到的机械应变激活。我们发现，在野生型小鼠体内胫骨机械负荷后，特异性NOTCH靶基因的表达被诱导。我们进一步应用机械应变，通过循环拉伸在人骨髓间充质干细胞（BMSCs）在体外通过使用生物反应器系统和检测NOTCH靶基因表达的上调。通过γ-分泌酶抑制剂GSI XII抑制原代BMSC以及端粒酶永生化的人BMSC（hMSC-TERT）中的NOTCH通路阻断了机械转导并调节了肌动蛋白细胞骨架组织。短发夹RNA基因沉默鉴定了NOTCH 2作为介导NOTCH对hMSC-TERT细胞作用的关键受体。我们的数据表明，NOTCH激活和人类骨髓间充质干细胞的机械转导之间的功能联系。我们认为，NOTCH信号是一个重要的贡献分子机制，介导骨形成的机械应变。
Skeletal development and remodeling of adult bone are critically controlled by activated NOTCH signaling in genetically modified mice. It is yet unclear whether NOTCH signaling is activated by mechanical strain sensed by bone cells. We found that expression of specific NOTCH target genes is induced after in vivo tibial mechanical loading in wild-type mice. We further applied mechanical strain through cyclic stretching in human bone marrow-derived mesenchymal stromal cells (BMSCs) in vitro by using a bioreactor system and detected upregulation of NOTCH target gene expression. Inhibition of the NOTCH pathway in primary BMSCs as well as telomerase-immortalized human BMSCs (hMSC-TERT) through the gamma-secretase inhibitor GSI XII blocked mechanotransduction and modulated actin cytoskeleton organization. Short-hairpin RNA gene silencing identified NOTCH2 as the key receptor mediating NOTCH effects on hMSC-TERT cells. Our data indicate a functional link between NOTCH activation and mechanotransduction in human BMSCs. We suggest that NOTCH signaling is an important contributor to molecular mechanisms that mediate the bone formation response to mechanical strain.