Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype
Authors: Kang Ting
Chenshuang Li
Eric C Chen
Kevin S Lee
Zhong Zheng
Aaron W James
Grace X Chang
Hsin Chuan Pan
Zhihe Zhao
Emily A Berthiaume
Yao Chen
Feng Chen
Wenlu Jiang
Chia Soo
Joyce Z Wang
Xinli Zhang
Weiming Li
Journal: Signal Transduction and Targeted Therapy (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Fetal-like phenotype; Fibromodulin; Scar reduction; Transforming growth factor β1; Wound healing.
Affiliations: Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA., UCLA Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA., Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA., State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P. R. China., Department of Emergency Medicine, Highland General Hospital, Oakland, CA 94602, USA., David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Central Laboratory, School of Stomatology, Peking University, Beijing 100081, P. R. China., Department of Orthopaedics, the First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.

Abstract:  Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair. 

Retracted: No

PubPeer comments:
 In Figures 5a, 5d, 5e, 6a and 6b, three sets of Gapdh images were duplicated (highlighted in red, blue and yellow frames). The same Gapdh blots were used for different treatments ( 6h and 24h) in Figure 5d. Worse yet, the authors intentionally flipped the 6h treatment Gapdh blot in Figure 5a (highlighted in yellow), and duplicated the flipped image in Figure 5e, 6a and 6b. ![file] ![file] ,