title: N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells.
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.
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Brian D
authors.identifier: http://orcid.org/0000-0003-2083-0039
authors.initials: BD
authors.lastname: Cosgrove
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Keeley L
authors.initials: KL
authors.lastname: Mui
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tristan P
authors.initials: TP
authors.lastname: Driscoll
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Caliari
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kush D
authors.initials: KD
authors.lastname: Mehta
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Mauck
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism*; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology; D055595:Mechanical Phenomena; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D008745:Methylation
chemical_list: D015820:Cadherins; D006820:Hyaluronic Acid