Therapeutic Silencing of p120 in Fascia Fibroblasts Ameliorates Tissue Repair

Published:November 25, 2022DOI:
      Deep skin wounds rapidly heal by mobilizing extracellular matrix and cells from the fascia, deep beneath the dermal layer of the skin, to form scars. Despite wounds being an extensively studied area and an unmet clinical need, the biochemistry driving this patch-like repair remains obscure. Lacking also are efficacious therapeutic means to modulate scar formation in vivo. In this study, we identify a central role for p120 in mediating fascia mobilization and wound repair. Injury triggers p120 expression, largely within engrailed-1 lineage-positive fibroblasts of the fascia that exhibit a supracellular organization. Using adeno-associated virus‒mediated gene silencing, we show that p120 establishes the supracellular organization of fascia engrailed-1 lineage-positive fibroblasts, without which fascia mobilization is impaired. Gene silencing of p120 in fascia fibroblasts disentangles their supracellular organization, reducing the transfer of fascial cells and extracellular matrix into wounds and augmenting wound healing. Our findings place p120 as essential for fascia mobilization, opening, to our knowledge, a previously unreported therapeutic avenue for targeted intervention in the treatment of a variety of skin scar conditions.


      AAV (adeno-associated virus), ECM (extracellular matrix), PIV (particle image velocimetry), shRNA (short hairpin RNA)
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        • Anastasiadis P.Z.
        • Moon S.Y.
        • Thoreson M.A.
        • Mariner D.J.
        • Crawford H.C.
        • Zheng Y.
        • et al.
        Inhibition of RhoA by p120 catenin.
        Nat Cell Biol. 2000; 2: 637-644
        • Correa-Gallegos D.
        • Jiang D.
        • Christ S.
        • Ramesh P.
        • Ye H.
        • Wannemacher J.
        • et al.
        Patch repair of deep wounds by mobilized fascia.
        Nature. 2019; 576: 287-292
        • Dvorak H.F.
        Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
        N Engl J Med. 1986; 315: 1650-1659
        • Dvorak H.F.
        Tumors: wounds that do not heal-redux.
        Cancer Immunol Res. 2015; 3: 1-11
        • Eming S.A.
        • Martin P.
        • Tomic-Canic M.
        Wound repair and regeneration: mechanisms, signaling, and translation.
        Sci Transl Med. 2014; 6: 265sr6
        • Galeano M.
        • Deodato B.
        • Altavilla D.
        • Cucinotta D.
        • Arsic N.
        • Marini H.
        • et al.
        Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse.
        Diabetologia. 2003; 46: 546-555
        • Gritsenko P.G.
        • Atlasy N.
        • Dieteren C.E.J.
        • Navis A.C.
        • Venhuizen J.H.
        • Veelken C.
        • et al.
        p120-catenin-dependent collective brain infiltration by glioma cell networks.
        Nat Cell Biol. 2020; 22: 97-107
        • Grosheva I.
        • Shtutman M.
        • Elbaum M.
        • Bershadsky A.D.
        p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell-cell contact formation and regulation of cell locomotion.
        J Cell Sci. 2001; 114: 695-707
        • Gurtner G.C.
        • Werner S.
        • Barrandon Y.
        • Longaker M.T.
        Wound repair and regeneration.
        Nature. 2008; 453: 314-321
        • Jazwa A.
        • Kucharzewska P.
        • Leja J.
        • Zagorska A.
        • Sierpniowska A.
        • Stepniewski J.
        • et al.
        Combined vascular endothelial growth factor-A and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice.
        Genet Vaccines Ther. 2010; 8: 6
        • Jiang D.
        • Christ S.
        • Correa-Gallegos D.
        • Ramesh P.
        • Kalgudde Gopal S.
        • Wannemacher J.
        • et al.
        Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin.
        Nat Commun. 2020; 11: 5653
        • Jiang D.
        • Correa-Gallegos D.
        • Christ S.
        • Stefanska A.
        • Liu J.
        • Ramesh P.
        • et al.
        Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring.
        Nat Cell Biol. 2018; 20: 422-431
        • Jiang D.
        • Rinkevich Y.
        Furnishing wound repair by the subcutaneous fascia.
        Int J Mol Sci. 2021; 22: 9006
        • Keswani S.G.
        • Balaji S.
        • Le L.
        • Leung A.
        • Lim F.Y.
        • Habli M.
        • et al.
        Pseudotyped adeno-associated viral vector tropism and transduction efficiencies in murine wound healing.
        Wound Repair Regen. 2012; 20: 592-600
        • Kumar S.
        • Mahendra G.
        • Nagy T.R.
        • Ponnazhagan S.
        Osteogenic differentiation of recombinant adeno-associated virus 2-transduced murine mesenchymal stem cells and development of an immunocompetent mouse model for ex vivo osteoporosis gene therapy.
        Hum Gene Ther. 2004; 15: 1197-1206
        • Kuzmin D.A.
        • Shutova M.V.
        • Johnston N.R.
        • Smith O.P.
        • Fedorin V.V.
        • Kukushkin Y.S.
        • et al.
        The clinical landscape for AAV gene therapies.
        Nat Rev Drug Discov. 2021; 20: 173-174
        • Marshall C.D.
        • Hu M.S.
        • Leavitt T.
        • Barnes L.A.
        • Lorenz H.P.
        • Longaker M.T.
        Cutaneous scarring: basic science, current treatments, and future directions.
        Adv Wound Care (New Rochelle). 2018; 7: 29-45
        • Mcmahon J.M.
        • Conroy S.
        • Lyons M.
        • Greiser U.
        • O’Shea C.
        • Strappe P.
        • et al.
        Gene transfer into rat mesenchymal stem cells: a comparative study of viral and nonviral vectors.
        Stem Cells and Development. 2006; 15: 87-96
        • Monstrey S.
        • Middelkoop E.
        • Vranckx J.J.
        • Bassetto F.
        • Ziegler U.E.
        • Meaume S.
        • et al.
        Updated scar management practical guidelines: non-invasive and invasive measures.
        J Plast Reconstr Aesthet Surg. 2014; 67: 1017-1025
        • Myster S.H.
        • Cavallo R.
        • Anderson C.T.
        • Fox D.T.
        • Peifer M.
        Drosophila p120catenin plays a supporting role in cell adhesion but is not an essential adherens junction component.
        Journal of Cell Biology. 2003; 160: 433-449
        • Ozaki C.
        • Yoshioka M.
        • Tominaga S.
        • Osaka Y.
        • Obata S.
        • Suzuki S.T.
        p120-Catenin is essential for N-cadherin-mediated formation of proper junctional structure, thereby establishing cell polarity in epithelial cells.
        Cell Struct Funct. 2010; 35: 81-94
        • Pettitt J.
        • Cox E.A.
        • Broadbent I.D.
        • Flett A.
        • Hardin J.
        The Caenorhabditis elegans p120 catenin homologue, JAC-1, modulates cadherin-catenin function during epidermal morphogenesis.
        J Cell Biol. 2003; 162: 15-22
        • Ramesh P.
        • Ye H.
        • Dasgupta B.
        • Machens H.G.
        • Rinkevich Y.
        Visualizing scar development using SCAD assay - an ex-situ skin scarring assay.
        J Vis Exp. 2022; : 182
        • Sen C.K.
        Human wounds and its burden: an updated compendium of estimates.
        Adv Wound Care (New Rochelle). 2019; 8: 39-48
        • Stender S.
        • Murphy M.
        • O’Brien T.
        • Stengaard C.
        • Ulrich-Vinther M.
        • Søballe K.
        • et al.
        Adeno-associated viral vector transduction of human mesenchymal stem cells.
        Eur Cell Mater. 2007; 13 (discussion 99): 93-99
        • Thoreson M.A.
        • Anastasiadis P.Z.
        • Daniel J.M.
        • Ireton R.C.
        • Wheelock M.J.
        • Johnson K.R.
        • et al.
        Selective uncoupling of p120(ctn) from E-cadherin disrupts strong adhesion.
        J Cell Biol. 2000; 148: 189-202
        • Wan L.
        • Jiang D.
        • Correa-Gallegos D.
        • Ramesh P.
        • Zhao J.
        • Ye H.
        • et al.
        Connexin43 gap junction drives fascia mobilization and repair of deep skin wounds.
        Matrix Biol. 2021; 97: 58-71
        • Wang D.
        • Tai P.W.L.
        • Gao G.
        Adeno-associated virus vector as a platform for gene therapy delivery.
        Nat Rev Drug Discov. 2019; 18: 358-378
        • Yanagisawa M.
        • Anastasiadis P.Z.
        J Cell Biol. p120 catenin is essential for mesenchymal cadherin-mediated regulation of cell motility and invasiveness. 2006; 174: 1087-1096