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

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 mesen...

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Published inNature materials Vol. 15; no. 12; pp. 1297 - 1306
Main Authors Cosgrove, Brian D, Mui, Keeley L, Driscoll, Tristan P, Caliari, Steven R, Mehta, Kush D, Assoian, Richard K, Burdick, Jason A, Mauck, Robert L
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.12.2016
Subjects
Adhesives
Animals
Biomechanical Phenomena
Biomedical materials
Biophysics
Cadherins - metabolism
Cattle
Cell adhesion & migration
Cell Adhesion - drug effects
Cues
Electrochemical machining
Evolution
Extracellular Matrix - drug effects
Extracellular Matrix - metabolism
Fibronectin
Hyaluronic Acid - chemistry
Hyaluronic Acid - pharmacology
Materials science
Mechanical Phenomena
Mesenchymal Stem Cells - cytology
Mesenchymal Stem Cells - drug effects
Methylation
Perception
Signal transduction
Stem cells
Stiffness
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Summary: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.
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ISSN:1476-1122
1476-4660
DOI:10.1038/nmat4725