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Mechanics Regulate Human Embryonic Stem Cell Self-Organization to Specify Mesoderm

73 Pages Posted: 2 Mar 2020 Publication Status: Review Complete

See all articles by Jonathon M. Muncie

Jonathon M. Muncie

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration

Nadia M.E. Ayad

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration

Johnathon N. Lakins

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration

Valerie M. Weaver

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration

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Abstract

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-adhesion 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.

Keywords: Human embryonic stem cells, self-organization, gastrulation, mesoderm, polyacrylamide hydrogels, tissue patterning, cytoskeletal tension, traction force microscopy

Suggested Citation

Muncie, Jonathon M. and Ayad, Nadia M.E. and Lakins, Johnathon N. and Weaver, Valerie M., Mechanics Regulate Human Embryonic Stem Cell Self-Organization to Specify Mesoderm. Available at SSRN: https://ssrn.com/abstract=3543833 or http://dx.doi.org/10.2139/ssrn.3543833
This version of the paper has not been formally peer reviewed.

Jonathon M. Muncie

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration ( email )

United States

Nadia M.E. Ayad

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration ( email )

United States

Johnathon N. Lakins

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration ( email )

United States

Valerie M. Weaver (Contact Author)

University of California, San Francisco (UCSF) - Center for Bioengineering and Tissue Regeneration ( email )

United States

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