title: YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography.
abstract: Native vascular extracellular matrices (vECM) consist of elastic fibers that impart varied topographical properties, yet most in vitro models designed to study the effects of topography on cell behavior are not representative of native architecture. Here, we engineer an electrospun elastin-like protein (ELP) system with independently tunable, vECM-mimetic topography and demonstrate that increasing topographical variation causes loss of endothelial cell-cell junction organization. This loss of VE-cadherin signaling and increased cytoskeletal contractility on more topographically varied ELP substrates in turn promote YAP activation and nuclear translocation, resulting in significantly increased endothelial cell migration and proliferation. Our findings identify YAP as a required signaling factor through which fibrous substrate topography influences cell behavior and highlights topography as a key design parameter for engineered biomaterials.
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Shamik
authors.initials: S
authors.lastname: Mascharak
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Benitez
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Proctor
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Madl
authors.affiliation: Biophysics Graduate Group, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Hu
authors.affiliation: Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Ruby E
authors.initials: RE
authors.lastname: Dewi
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Manish J
authors.initials: MJ
authors.lastname: Butte
authors.affiliation: Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA. Electronic address: heilshorn@stanford.edu.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Heilshorn
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D040761:Biomimetic Materials / Q000737:chemistry; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D005109:Extracellular Matrix / Q000737:chemistry*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013314:Stress, Mechanical; D013499:Surface Properties; D054457:Tissue Scaffolds; D000091102:YAP-Signaling Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat
keywords: Cell matrix interactions; Electrospinning; Mechanotransduction signaling; Substrate topography