Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level forces. Whether cell tension regulates development by modifying morphogen signaling is less clear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization, which motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that recapitulate the biophysical properties of the early embryo and mediate the self-organization of “gastrulation-like” nodes in cultured hESCs. Tissue geometries that generated local nodes of high cell-adhesion tension directed the spatial patterning of the BMP4-dependent “gastrulation-like” phenotype by enhancing phosphorylation and junctional release of β-catenin to promote Wnt signaling and mesoderm specification. Furthermore, direct force application via mechanical stretching promoted BMP-dependent mesoderm specification, confirming that tissue-level forces can directly regulate cell fate specification in early human development.

胚胎发生是由形态发生素引导的，形态发生素在确定的组织几何形状内诱导分化。组织组织由细胞与细胞和细胞与细胞外基质（ECM）粘附介导，并受到细胞张力和组织水平力的调节。细胞张力是否通过改变形态发生素信号传导来调节发育尚不清楚。人类胚胎干细胞（hESC）表现出内在的自组织能力，这促使它们用作早期人类胚胎发生的易处理模型。我们设计了图案化的基质，可以概括早期胚胎的生物物理特性，并介导培养 hESC 中“原肠胚形成样”节点的自组织。产生高细胞粘附张力局部节点的组织几何形状通过增强β-连环蛋白的磷酸化和连接释放来促进 Wnt 信号传导和中胚层规范，从而指导 BMP4 依赖性“原肠胚形成样”表型的空间模式。此外，通过机械拉伸直接施加力促进了 BMP 依赖性中胚层规范，证实组织水平的力可以直接调节人类早期发育中的细胞命运规范。