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Fibromodulin Selectively Promotes Myofibroblast Apoptosis During Cutaneous Wound Healing
Wenlu Jiang, BDS, PhD1,2, Yao Chen, BDS, PhD2, Chenchao Wang, MD2,3, Kevin S. Lee, DDS, MS2, Joyce Z. Wang, MD4, Seungjun Lee, BS5, Kang Ting, D.M.D., D.Med.Sc2, Zhihe Zhao, DDS, PhD1, Chia Soo, MD, FACS6, Zhong Zheng, PhD2.
1State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, China, 2Division of Growth and Development, School of Dentistry, University of California, Los Angeles, CA, USA, 3Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China, 4Department of Emergency Medicine, Highland General Hospital, Oakland, CA, USA, 5Department of Chemistry and Biochemistry, School of Letters and Science, University of California, Los Angeles, CA, USA, 6Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Objective: Cutaneous scar formation is a significant clinical concern with substantial functional and psychosocial sequelae that translates to an annual cost of $3 billion in the U.S alone. In particular, trauma and burn often lead to severe hypertrophic scarring with disfigurement and dysfunction. The persistence and accumulation of myofibroblasts after reepithelization have been considered to play a critical role in excessive extracellular matrix (ECM) deposition and scar contraction that comprise hypertrophic scarring. Our previous studies indicated that fibromodulin (FMOD) plays an essential role in fetal and adult wound healing. For instance, FMOD promotes dermal fibroblast migration and myofibroblast conversion and contraction that lead to fast wound closure and reduced wound size. This study aimed to further explore the role of FMOD in cutaneous wound healing at the regeneration stage, especially rapid clearance of myofibroblast from the wound site after wound closure, and evaluate the clinical potential of FMOD-based therapeutics.
Method: Full-thickness skin ellipses with the underlying panniculuscarnosus muscle were excised to generate primary closure wounds in not only mouse and rat models but also pig models with high-mechanical loading. Wounds were treated once with FMOD or PBS control at the time of injury. Myofibroblast accumulation was evaluated by immunohistochemical staining against α-smooth muscle actin (α-SMA). RNA was isolated from the wounds and subjected to real-time PCR to determineinterleukin (IL)1β expression. Meanwhile, primary rat dermal fibroblasts (RDFs) and a human hTERT immortalized dermal fibroblast cell line, BJ-5ta, were converted into myofibroblasts by transforming growth factor (TGF)β1 stimulation. The apoptosis of yield myofibroblasts with or without FMOD was measured by terminaldeoxynucleotidyltransferasedUTP nick end labeling (TUNEL). Gene expression was assessed by real-time PCR.
Results: In vivo, Fmod-/- mouse wounds representing a lost-of-function model presented markedly increased myofibroblasts after wound closure compared with wild-type (WT) controls. Intradermal injection of FMOD representing gain-of-function models led to significantly decreased myofibroblast accumulation in the wound areas of multiple animal species, including WT mice and Fmod-/- mice, rats and pigs with high-mechanical loading wounds. Moreover, FMOD injection significantly stimulated Il1β expression, which likely contributed to the diminished
number of myofibroblasts. In vitro, FMOD alone stimulated myofibroblast (but not fibroblast) apoptosis as effectively as IL1β. Remarkably, even in the presence of TGFβ1 that completely blocked the effect of IL1β, FMOD promoted myofibroblast apoptosis. Meanwhile, IL1 receptor antagonist (IL1RA) fully rescued myofibroblasts from FMOD-induced apoptosis and blocked FMOD-stimulated myofibroblast IL1β expression. Thus, FMOD selectively promoted apoptosis of myofibroblasts but not fibroblasts via an IL1β-dependent pathway.
Conclusion: FMOD accelerates myofibroblast clearance during cutaneous wound healing that significantly reduces scarring, especially hypertrophic scarring, through an IL1β-dependent pathway. Since among mammalian skin porcine skin most closely approximates human skin in anatomic structure, mechanical properties and wound healing and pig models are required by the U.S. Food and Drug Administration (FDA) for human skin product testing, our current study presents a remarkable translational potential of FMOD for human scar management.
Keywords: Fibromodulin, cutaneous wound healing, apoptosis


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