title: Cellular forces and matrix assembly coordinate fibrous tissue repair.
abstract: Planar in vitro models have been invaluable tools to identify the mechanical basis of wound closure. Although these models may recapitulate closure dynamics of epithelial cell sheets, they fail to capture how a wounded fibrous tissue rebuilds its 3D architecture. Here we develop a 3D biomimetic model for soft tissue repair and demonstrate that fibroblasts ensconced in a collagen matrix rapidly close microsurgically induced defects within 24 h. Traction force microscopy and time-lapse imaging reveal that closure of gaps begins with contractility-mediated whole-tissue deformations. Subsequently, tangentially migrating fibroblasts along the wound edge tow and assemble a progressively thickening fibronectin template inside the gap that provide the substrate for cells to complete closure. Unlike previously reported mechanisms based on lamellipodial protrusions and purse-string contraction, our data reveal a mode of stromal closure in which coordination of tissue-scale deformations, matrix assembly and cell migration act together to restore 3D tissue architecture.
authors.affiliation: Institute of Robotics and Intelligent Systems, Eidgenössische Technische Hochschule Zürich, 8092 Zurich, Switzerland.
authors.forename: Mahmut Selman
authors.initials: MS
authors.lastname: Sakar
authors.affiliation: Department of Biomedical Engineering, Boston University, 36 Cummington Mall, Boston, Massachusetts 02215, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Eyckmans
authors.affiliation: Institute of Robotics and Intelligent Systems, Eidgenössische Technische Hochschule Zürich, 8092 Zurich, Switzerland.
authors.forename: Roel
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Laboratory for Urologic Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital, Zurich 8091, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eberli
authors.affiliation: Institute of Robotics and Intelligent Systems, Eidgenössische Technische Hochschule Zürich, 8092 Zurich, Switzerland.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Nelson
authors.affiliation: Department of Biomedical Engineering, Boston University, 36 Cummington Mall, Boston, Massachusetts 02215, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D051379:Mice; D018625:Microscopy, Atomic Force; D008866:Microsurgery; D008962:Models, Theoretical; D041681:NIH 3T3 Cells; D017695:Soft Tissue Injuries / Q000378:metabolism / Q000503:physiopathology*; D059008:Time-Lapse Imaging; D014945:Wound Healing / Q000502:physiology*
chemical_list: D015820:Cadherins; C489083:Cdh2 protein, mouse; D024042:Collagen Type I; D005353:Fibronectins