Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment
Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment
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DOI：
10.1016/s1534-5807(04)00075-9
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发表时间：
2004-04-01
影响因子：
11.8
通讯作者：
Chen, CS
中科院分区：
文献类型：
--
作者：
McBeath, R;Pirone, DM;Chen, CS
干细胞向不同谱系的承诺是由局部组织微环境中的许多线索调节的。在这里，我们证明了细胞形状调节人间充质干细胞（hMSCs）向脂肪细胞或成骨细胞命运的承诺。被允许粘附、变平和扩散的hMSCs发生成骨作用，而未扩散的圆形细胞变成脂肪细胞。细胞形状通过调节内源性RhoA活性来调节谱系承诺的开关。表达显性阴性RhoA使hMSCs成为脂肪细胞，而组成型活性RhoA则导致成骨。然而，RhoA介导的脂肪生成或成骨分别取决于圆形或扩散形状，而RhoA效应物ROCK的组成性激活诱导成骨与细胞形状无关。RhoA-ROCK承诺信号需要肌动蛋白-肌球蛋白产生的张力。这些研究表明，在发育和成体环境中经历的机械信号，包括细胞形状、细胞骨架张力和RhoA信号，对干细胞命运的承诺是不可或缺的。
Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.