title: Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor.
abstract: Scarring is a long-lasting problem in higher animals, and reductionist approaches could aid in developing treatments. Here, we show that copolymerization of collagen I with polyacrylamide produces minimal matrix models of scars (MMMS), in which fractal-fibre bundles segregate heterogeneously to the hydrogel subsurface. Matrix stiffens locally-as in scars-while allowing separate control over adhesive-ligand density. The MMMS elicits scar-like phenotypes from mesenchymal stem cells (MSCs): cells spread and polarize quickly, increasing nucleoskeletal lamin-A yet expressing the 'scar marker' smooth muscle actin (SMA) more slowly. Surprisingly, expression responses to MMMS exhibit less cell-to-cell noise than homogeneously stiff gels. Such differences from bulk-average responses arise because a strong SMA repressor, NKX2.5, slowly exits the nucleus on rigid matrices. NKX2.5 overexpression overrides rigid phenotypes, inhibiting SMA and cell spreading, whereas cytoplasm-localized NKX2.5 mutants degrade in well-spread cells. MSCs thus form a 'mechanical memory' of rigidity by progressively suppressing NKX2.5, thereby elevating SMA in a scar-like state.
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: P C Dave P
authors.initials: PC
authors.lastname: Dingal
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bradshaw
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sangkyun
authors.initials: S
authors.lastname: Cho
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Raab
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amnon
authors.initials: A
authors.lastname: Buxboim
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Swift
authors.affiliation: Biophysical Engineering Labs for Molecular &Cell Biophysics and NanoBio-Polymers, Department of Chemical and Biomolecular Engineering and Graduate Group in Physics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002921:Cicatrix / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I / Q000737:chemistry; D005109:Extracellular Matrix / Q000737:chemistry*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D055153:Stem Cell Niche; D014157:Transcription Factors / Q000378:metabolism*; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D000199:Actins; D024042:Collagen Type I; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099166:Polyacrylamides; C484469:Nkx2-5 protein, mouse; C544013:alpha-smooth muscle actin, mouse