title: Mesenchymal stromal cells reverse hypoxia-mediated suppression of α-smooth muscle actin expression in human dermal fibroblasts.
abstract: During wound healing, fibroblasts deposit extracellular matrix that guides angiogenesis and supports the migration and proliferation of cells that eventually form the scar. They also promote wound closure via differentiation into α-smooth muscle actin (SMA)-expressing myofibroblasts, which cause wound contraction. Low oxygen tension typical of chronic nonhealing wounds inhibits fibroblast collagen production and differentiation. It has been suggested that hypoxic mesenchymal stromal cells (MSCs) secrete factors that promote wound healing in animal models; however, it is unclear whether these factors are equally effective on the target cells in a hypoxic wound environment. Here we investigated the impact of MSC-derived soluble factors on the function of fibroblasts cultured in hypoxic fibroblast-populated collagen lattices (FPCLs). Hypoxia alone significantly decreased FPCL contraction and α-SMA expression. MSC-conditioned medium restored hypoxic FPCL contraction and α-SMA expression to levels similar to normoxic FPCLs. SB431542, an inhibitor of transforming growth factor-β1 (TGF-β1)-mediated signaling, blocked most of the MSC effect on FPCL contraction, while exogenous TGF-β1 at levels similar to that secreted by MSCs reproduced the MSC effect. These results suggest that TGF-β1 is a major paracrine signal secreted by MSCs that can restore fibroblast functions relevant to the wound healing process and that are impaired in hypoxia.
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Renea A
authors.initials: RA
authors.lastname: Faulknor
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Olekson
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Nir I
authors.initials: NI
authors.lastname: Nativ
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ghodbane
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Gray
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: fberthia@rci.rutgers.edu.
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
mesh_terms: D000199:Actins / Q000378:metabolism*; D000464:Alginates; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D018914:Cells, Immobilized; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing
chemical_list: D000199:Actins; D000464:Alginates; D017077:Culture Media, Conditioned; D006603:Hexuronic Acids; D053773:Transforming Growth Factor beta1; D020723:Glucuronic Acid; D003094:Collagen
keywords: Fibroblasts; Hypoxia; Mesenchymal stromal cells; Transforming growth factor-β1