title: Tissue Mechanics Orchestrate Wnt-Dependent Human Embryonic Stem Cell Differentiation.
abstract: Regenerative medicine is predicated on understanding the mechanisms regulating development and applying these conditions to direct stem cell fate. Embryogenesis is guided by cell-cell and cell-matrix interactions, but it is unclear how these physical cues influence stem cells in culture. We used human embryonic stem cells (hESCs) to examine whether mechanical features of the extracellular microenvironment could differentially modulate mesoderm specification. We found that, on a hydrogel-based compliant matrix, hESCs accumulate β-catenin at cell-cell adhesions and show enhanced Wnt-dependent mesoderm differentiation. Mechanistically, Src-driven ubiquitination of E-cadherin by Cbl-like ubiquitin ligase releases P120-catenin to facilitate transcriptional activity of β-catenin, which initiates and reinforces mesoderm differentiation. By contrast, on a stiff hydrogel matrix, hESCs show elevated integrin-dependent GSK3 and Src activity that promotes β-catenin degradation and inhibits differentiation. Thus, we found that mechanical features of the microenvironmental matrix influence tissue-specific differentiation of hESCs by altering the cellular response to morphogens.
authors.affiliation: Center for Bioengineering and Tissue Regeneration and Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Laralynne
authors.initials: L
authors.lastname: Przybyla
authors.affiliation: Center for Bioengineering and Tissue Regeneration and Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Johnathon N
authors.initials: JN
authors.lastname: Lakins
authors.affiliation: Center for Bioengineering and Tissue Regeneration and Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Anatomy, Bioengineering, and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: valerie.weaver@ucsf.edu.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D000066673:Cell Self Renewal; D002642:Chick Embryo; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D051153:Wnt Proteins; D051176:beta Catenin; D019061:src-Family Kinases