Material Properties of the Cell Dictate Stress-induced Spreading and Differentiation in Embryonic Stem Cells Growing Evidence Suggests That Physical Microenvironments and Mechanical Stresses, in Addition to Soluble Factors, Help Direct Mesenchymal-stem-cell Fate. However, Biological Responses to a L
Material Properties of the Cell Dictate Stress-induced Spreading and Differentiation in Embryonic Stem Cells Growing Evidence Suggests That Physical Microenvironments and Mechanical Stresses, in Addition to Soluble Factors, Help Direct Mesenchymal-stem-cell Fate. However, Biological Responses to a L
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通讯作者：
F. Chowdhury;S. Na;Dong Li;Y. Poh;Tetsuya S. Tanaka;Fei Wang;Ningwang
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作者：
F. Chowdhury;S. Na;Dong Li;Y. Poh;Tetsuya S. Tanaka;Fei Wang;Ningwang
对于传播反应至关重要。施加的压力导致 mES 细胞中 oct3/4 基因下调。我们的研究结果表明，细胞的柔软度决定了细胞对力的敏感性，这表明局部的小力在软胚胎的早期发育中可能比以前认为的更重要。胚胎干 (ES) 细胞因其多能性和潜在的治疗应用而成为生物学的主要关注点之一 1-3。尽管众所周知，可溶性因子在干细胞分化中至关重要 4,5 ，但最近的证据表明，细胞的物理微环境（例如形状限制或基质硬度）有助于指导间充质干细胞的命运 6,7 。然而，这些细胞处于细胞谱系规范的下游，与 ES 细胞相比，自我更新和分化能力有限。我们关注多能 ES 细胞，因为人们对这些细胞如何响应机械力知之甚少。了解 ES 细胞对力做出反应的基本过程对于理解谱系决定和发育的机制至关重要，因为这些细胞源自原肠胚形成之前囊胚的内细胞团，原肠胚形成会启动动态细胞重排。众所周知，活细胞会响应机械力而改变其形状和功能。例如，整个内皮细胞上的单向层流剪切流应力有利于细胞在流动方向上铺展和伸长 8. 血管平滑肌细胞的单轴拉伸使细胞在拉伸方向上伸长 9. 整个间充质干细胞的循环单轴拉伸增加了细胞增殖和平滑肌细胞标记物的表达 10. 最近，有报道称，整个造血祖细胞上的流体剪切应力促进了胚胎的形成造血 11. 然而，ES 细胞是否以及如何对局部机械应力做出反应仍然难以捉摸。在过去十年左右的时间里，基质刚性在细胞功能中的重要性已变得越来越明显7,12–14。细胞外基质的物理和机械信号通过未知机制转变成细胞内流变学和生化变化，但可能是通过基于粘着斑的蛋白质 15 和其他蛋白质的构象变化或展开。另一方面，一些研究人员提出细胞内流变特性对于理解细胞行为至关重要 16-18。因此，有人认为内在的细胞内材料机械特性控制着细胞的行为和功能。然而，没有实验数据可以明确表明活细胞固有的细胞内流变特性从根本上......
were essential in the spreading response. The applied stress led to oct3/4 gene downregulation in mES cells. Our findings demonstrate that cell softness dictates cellular sensitivity to force, suggesting that local small forces might have far more important roles in early development of soft embryos than previously appreciated. E mbryonic stem (ES) cells are one of the principle focuses in biology because of their pluripotency and potential therapeutic applications 1–3. Although it is known that soluble factors are critical in stem-cell differentiation 4,5 , recent evidence shows that the physical microenvironment of the cells (for example, shape constraint or substrate stiffness) helps direct the fate of mesenchymal stem cells 6,7. These cells, however, are downstream in cell-lineage specifications, and have limited self-renewal and differentiation capacities in comparison to ES cells. We focus on pluripotent ES cells because little is known about how these cells respond to mechanical forces. Understanding the fundamental processes by which ES cells respond to force is crucial in understanding mechanisms of lineage determination and development as these cells are derived from the inner cell mass of blastocysts before gastrulation, which initiates dynamic cellular rearrangements. It is known that living cells alter their shapes and functions in response to mechanical forces. For example, unidirectional laminar shear flow stresses over a whole endothelial cell facilitate cell spreading and elongation in the direction of the flow 8. Uniaxial stretching of a vascular smooth muscle cell elongates the cell in the direction of stretching 9. Cyclic uniaxial stretching of whole mesenchymal stem cells increases cell proliferation and expression of smooth-muscle-cell markers 10. Recently, it was reported that fluid shear stress over whole haematopoietic progenitor cells promotes embryonic haematopoiesis 11. However, whether and how ES cells respond to a localized mechanical stress remain elusive. During the past decade or so, the importance of substrate rigidity in cell functions has become increasingly clear 7,12–14. The physical and mechanical cues of the extracellular matrix are transduced into intracellular rheological and biochemical changes through unknown mechanisms, but probably through conformational changes or unfolding of focal adhesion-based proteins 15 and other proteins. On the other hand, several researchers have proposed that intracellular rheological properties are critical in understanding cellular behaviours 16–18. Therefore, it is suggested that intrinsic intracellular material mechanical properties govern cellular behaviour and functions. However, no experimental data are available to unequivocally show that intrinsic intracellular rheological properties of living cells are fundamentally …