title: Myofibroblasts contribute to but are not necessary for wound contraction.
abstract: Wound contraction facilitates tissue repair. The correct balance between too little contraction, which leads to non-healing wounds, and too much contraction, which leads to contractures, is important for optimal healing. Thus, understanding which cells cause wound contraction is necessary to optimize repair. Wound contraction is hypothesized to develop from myofibroblast (cells which express alpha-smooth muscle actin; ACTA2) contractility, while the role of fibroblast contractility is unknown. In this study, we utilized ACTA2 null mice to determine what role fibroblasts play in wound contraction. Human scar contractures were immunostained for ACTA2, beta-cytoplasmic actin (ACTB), and gamma-cytoplasmic actin (ACTG1). Full-thickness cutaneous wounds were created on dorsum of ACTA2(+/+) mice and strain-matching ACTA2(+/-) and ACTA2(-/-) mice. Wound contraction was quantified. Tissue was harvested for histologic, immunohistochemical and protein analysis. Compared with surrounding unwounded skin, human scar tissue showed increased expression of ACTA2, ACTB, and ACTG1. ACTA2 was focally expressed in clusters. ACTB and ACTG1 were widely, highly expressed throughout scar tissue. Wound contraction was significantly retarded in ACTA2(-/-) mice, as compared to ACTA2(+/+) controls. Control mice had increased epithelialization, cell proliferation, and neovascularization. ACTA2(-/-) mice had lower levels of apoptosis, and fewer total numbers of cells. Smaller amount of collagen deposition and immature collagen organization in ACTA2(-/-) mice demonstrate that wounds were more immature. These data demonstrate that myofibroblasts contribute to but are not necessary for wound contraction. Mechanisms by which fibroblasts promote wound contraction may include activation of contractile signaling pathways, which promote interaction between non-muscle myosin II and ACTB and ACTG1.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Mohamed M
authors.identifier: http://orcid.org/0000-0003-3547-2764
authors.initials: MM
authors.lastname: Ibrahim
authors.affiliation: Department of Burn Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Plastic and Reconstructive Surgery, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bond
authors.affiliation: Division of Plastic and Reconstructive Surgery, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Medina
authors.affiliation: Division of Plastic and Reconstructive Surgery, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.|Department of Burns and Reconstructive Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Licheng
authors.initials: L
authors.lastname: Ren
authors.affiliation: Division of Plastic and Reconstructive Surgery, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kokosis
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Selim
authors.affiliation: Division of Plastic and Reconstructive Surgery, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.|Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Levinson
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000502:physiology*; D018919:Neovascularization, Physiologic; D012867:Skin / Q000378:metabolism; D014945:Wound Healing; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; C558396:Acta2 protein, mouse; D000199:Actins; D015415:Biomarkers; D003094:Collagen