PT  - JOURNAL ARTICLE
AU  - Jonathon M. Muncie
AU  - Nadia M.E. Ayad
AU  - Johnathon N. Lakins
AU  - Valerie M. Weaver
TI  - Mechanics regulate human embryonic stem cell self-organization to specify mesoderm
AID  - 10.1101/2020.02.10.943076
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.10.943076
4099  - http://biorxiv.org/content/early/2020/02/11/2020.02.10.943076.short
4100  - http://biorxiv.org/content/early/2020/02/11/2020.02.10.943076.full
AB  - 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 β-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.Graphical AbstractHighlightsSubstrates that enhance cell-cell adhesion promote hESC self-organizationTissue nodes exhibiting high tension are predisposed to gastrulation inductionColony geometry dictates the localization of tension nodes to specify mesodermTension activates β-catenin and stimulates Wnt signaling to induce mesodermIn Brief Engineered 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 β-catenin to promote Wnt signaling.