Mechanics regulate human embryonic stem cell self-organization to specify mesoderm
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 force. Whether cell tension regulates development by directly influencing morphogen signaling remains unclear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization that motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that enhance cell-cell interactions to direct the self-organization of cultured hESCs into "gastrulation-like" nodes. Tissue geometries that generate local nodes of high cell-cell tension and induce these self-organized tissue nodes drive BMP4-dependent gastrulation by enhancing phosphorylation and nuclear translocation of {beta}-catenin to promote Wnt signaling and mesoderm specification. The findings underscore the interplay between tissue organization, cell tension, and morphogen-dependent differentiation, and demonstrate that cell- and tissue-level forces directly regulate cell fate specification in early human development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/943076v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@e21aaeorg.highwire.dtl.DTLVardef@45c41forg.highwire.dtl.DTLVardef@4ee902org.highwire.dtl.DTLVardef@a3837d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG HighlightsO_LISubstrates that enhance cell-cell adhesion promote hESC self-organization C_LIO_LITissue nodes exhibiting high tension are predisposed to gastrulation induction C_LIO_LIColony geometry dictates the localization of tension nodes to specify mesoderm C_LIO_LITension activates {beta}-catenin and stimulates Wnt signaling to induce mesoderm C_LI In BriefEngineered substrates that promote cell-cell adhesion and reconstitute epiblast tissue organization facilitate "gastrulation-like" morphogenesis in cultured hESCs. Tissue geometries that foster localized regions of high cell-cell tension potentiate BMP4-dependent mesoderm specification by enhancing phosphorylation and nuclear translocation of {beta}-catenin to promote Wnt signaling.