title: Filamin A Mediates Wound Closure by Promoting Elastic Deformation and Maintenance of Tension in the Collagen Matrix.
abstract: Cell-mediated remodeling and wound closure are critical for efficient wound healing, but the contribution of actin-binding proteins to contraction of the extracellular matrix is not defined. We examined the role of filamin A (FLNa), an actin filament cross-linking protein, in wound contraction and maintenance of matrix tension. Conditional deletion of FLNa in fibroblasts in mice was associated with ~4 day delay of full-thickness skin wound contraction compared with wild-type (WT) mice. We modeled the healing wound matrix using cultured fibroblasts plated on grid-supported collagen gels that create lateral boundaries, which are analogues to wound margins. In contrast to WT cells, FLNa knockdown (KD) cells could not completely maintain tension when matrix compaction was resisted by boundaries, which manifested as relaxed matrix tension. Similarly, WT cells on cross-linked collagen, which requires higher levels of sustained tension, exhibited approximately fivefold larger deformation fields and approximately twofold greater fiber alignment compared with FLNa KD cells. Maintenance of boundary-resisted tension markedly influenced the elongation of cell extensions: in WT cells, the number (~50%) and length (~300%) of cell extensions were greater than FLNa KD cells. We conclude that FLNa is required for wound contraction, in part by enabling elastic deformation and maintenance of tension in the matrix.
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada. Electronic address: hamid.mohammadi@utoronto.ca.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mohammadi
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vanessa I
authors.initials: VI
authors.lastname: Pinto
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004548:Elasticity; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D064448:Filamins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D013718:Tensile Strength / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: D064448:Filamins; D003094:Collagen