N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells

Nat Mater. 2016 Dec;15(12):1297-1306. doi: 10.1038/nmat4725. Epub 2016 Aug 15.

Abstract

During mesenchymal development, the microenvironment gradually transitions from one that is rich in cell-cell interactions to one that is dominated by cell-ECM (extracellular matrix) interactions. Because these cues cannot readily be decoupled in vitro or in vivo, how they converge to regulate mesenchymal stem cell (MSC) mechanosensing is not fully understood. Here, we show that a hyaluronic acid hydrogel system enables, across a physiological range of ECM stiffness, the independent co-presentation of the HAVDI adhesive motif from the EC1 domain of N-cadherin and the RGD adhesive motif from fibronectin. Decoupled presentation of these cues revealed that HAVDI ligation (at constant RGD ligation) reduced the contractile state and thereby nuclear YAP/TAZ localization in MSCs, resulting in altered interpretation of ECM stiffness and subsequent changes in downstream cell proliferation and differentiation. Our findings reveal that, in an evolving developmental context, HAVDI/N-cadherin interactions can alter stem cell perception of the stiffening extracellular microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Cadherins / metabolism*
  • Cattle
  • Cell Adhesion* / drug effects
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / pharmacology
  • Mechanical Phenomena*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Methylation

Substances

  • Cadherins
  • Hyaluronic Acid