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      Fibromodulin reduces scar size and increases scar tensile strength in normal and excessive‐mechanical‐loading porcine cutaneous wounds

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          Abstract

          Hypertrophic scarring is a major postoperative complication which leads to severe disfigurement and dysfunction in patients and usually requires multiple surgical revisions due to its high recurrence rates. Excessive‐mechanical‐loading across wounds is an important initiator of hypertrophic scarring formation. In this study, we demonstrate that intradermal administration of a single extracellular matrix ( ECM) molecule—fibromodulin ( FMOD) protein—can significantly reduce scar size, increase tensile strength, and improve dermal collagen architecture organization in the normal and even excessive‐mechanical‐loading red Duroc pig wound models. Since pig skin is recognized by the Food and Drug Administration as the closest animal equivalent to human skin, and because red Duroc pigs show scarring that closely resembles human proliferative scarring and hypertrophic scarring, FMOD‐based technologies hold high translational potential and applicability to human patients suffering from scarring—especially hypertrophic scarring.

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          Most cited references14

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          Fibroblasts and myofibroblasts in wound healing

          (Myo)fibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. (Myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. In addition to the secretion of the ECM, (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases, are able to remodel this ECM. (Myo)fibroblasts and their microenvironment form an evolving network during tissue repair, with reciprocal actions leading to cell differentiation, proliferation, quiescence, or apoptosis, and actions on growth factor bioavailability by binding, sequestration, and activation. In addition, the (myo)fibroblast phenotype is regulated by mechanical stresses to which they are subjected and thus by mechanical signaling. In pathological situations (excessive scarring or fibrosis), or during aging, this dialogue between the (myo)fibroblasts and their microenvironment may be altered or disrupted, leading to repair defects or to injuries with damaged and/or cosmetic skin alterations such as wrinkle development. The intimate dialogue between the (myo)fibroblasts and their microenvironment therefore represents a fascinating domain that must be better understood in order not only to characterize new therapeutic targets and drugs able to prevent or treat pathological developments but also to interfere with skin alterations observed during normal aging or premature aging induced by a deleterious environment.
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            Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis.

            Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one-week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20-fold) and cellular density (20-fold). The increased cellularity is accompanied by a four-fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53-null mice, with down-regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII-null mice. We conclude that mechanical loading early in the proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism.
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              Scarless fetal wound healing: a basic science review.

              Scar formation is a major medical problem that can have devastating consequences for patients. The adverse physiological and psychological effects of scars are broad, and there are currently no reliable treatments to prevent scarring. In contrast to adult wounds, early gestation fetal skin wounds repair rapidly and in the absence of scar formation. Despite extensive investigation, the exact mechanisms of scarless fetal wound healing remain largely unknown. For some time, it has been known that significant differences exist among the extracellular matrix, inflammatory response, cellular mediators, and gene expression profiles of fetal and postnatal wounds. These differences may have important implications in scarless wound repair.
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                Author and article information

                Contributors
                bsoo@ucla.edu
                zzheng@dentistry.ucla.edu
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                01 February 2018
                April 2018
                : 22
                : 4 ( doiID: 10.1111/jcmm.2018.22.issue-4 )
                : 2510-2513
                Affiliations
                [ 1 ] State Key Laboratory of Oral Diseases Department of Orthodontics West China Hospital of Stomatology Sichuan University Chengdu Sichuan China
                [ 2 ] Division of Growth and Development Section of Orthodontics School of Dentistry University of California, Los Angeles Los Angeles CA USA
                [ 3 ] Department of Orthopaedic Surgery CHA Bundang Medical Center CHA University Gyeonggi‐do South Korea
                [ 4 ] Department of Bioengineering School of Engineering University of California, Los Angeles Los Angeles CA USA
                [ 5 ] UCLA Division of Plastic and Reconstructive Surgery Department of Orthopaedic Surgery The Orthopaedic Hospital Research Center University of California, Los Angeles Los Angeles CA USA
                Author notes
                [*] [* ] Correspondence to: Chia SOO

                E‐mail: bsoo@ 123456ucla.edu

                Zhong ZHENG

                E‐mail: zzheng@ 123456dentistry.ucla.edu

                [†]

                Wenlu Jiang and Kang Ting contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-4905-3563
                Article
                JCMM13516
                10.1111/jcmm.13516
                5867110
                29392829
                69796ff6-d2e5-4d1e-a7c9-067441d1a872
                © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 October 2017
                : 20 November 2017
                Page count
                Figures: 1, Tables: 0, Pages: 4, Words: 2336
                Funding
                Funded by: Plastic Surgery Foundation
                Funded by: 2013 National Endowment for Plastic Surgery
                Award ID: 269698
                Funded by: NIH‐NIAMS
                Award ID: R44AR064126
                Funded by: NIH‐NIDCR
                Award ID: R44DE024692
                Award ID: R44DE026080
                Award ID: SB1DE026972
                Funded by: NIH‐NCRR
                Award ID: CJX1‐443835‐WS‐29646
                Funded by: NSF Major Research Instrumentation
                Award ID: CHE‐0722519
                Categories
                Short Communication
                Short Communications
                Custom metadata
                2.0
                jcmm13516
                April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.3 mode:remove_FC converted:25.03.2018

                Molecular medicine
                wound healing,tissue regeneration,scarring,hypertrophic scarring,fibromodulin
                Molecular medicine
                wound healing, tissue regeneration, scarring, hypertrophic scarring, fibromodulin

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