Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing

Abstract

In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss-and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of fibromodulin protein (FM) alone was capable of restoring scarless healing in lategestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-b1 expression and scarless repair, while low Fm levels correlated with increased TGF-b1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FMeTGF-b1 nexus plays in fetal-type scarless skin repair. (Am J Pathol 2016 http://dx

CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells

“…68, 69). Meanwhile, FMOD loss of function caused scarring in normally scarless earlygestational fetal wounds (69), while FMOD gain of function restored scarless healing to normally scar-prone late-gestational fetal wounds (69) as well as reduced adult scar formation by elicit-…”

Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte‐like cells

“…Though FMOD expression was found to be significant in young muscle tissues compared to old muscle tissues (13, 37), no direct correlation of FMOD effect on muscle has been reported in in vivo models. However, indirect evidences of FMOD's effect on ECM component assembly such as collagens and its involvement in wound healing is well reported in the literature (16, 38–40). In addition, its involvement in cellular reprograming has also been recently reported by Zheng et al (41).…”

Inflammation as an orchestrator of cutaneous scar formation: a review of the literature

“…Additionally, fibromodulin levels increase during healing in scarless fetal wounds, which have minimal inflammation, but remain low in scar-forming wounds which display a typical inflammatory response [ 149 ] . Lower fibromodulin levels have been reported in HTS from human subjects and animal models compared to normal tissue [ 150 , 151 ] , and mice lacking fibromodulin heal with more inflammation [ 152 ] and more scar formation [ 153 , 154 ] . Increasing fibromodulin levels via adenoviral overexpression or treating with recombinant fibromodulin has been shown to reduce scar formation in rabbit, mouse, and red Duroc pig wounds [ 153 – 156 ] .…”

“…Lower fibromodulin levels have been reported in HTS from human subjects and animal models compared to normal tissue [ 150 , 151 ] , and mice lacking fibromodulin heal with more inflammation [ 152 ] and more scar formation [ 153 , 154 ] . Increasing fibromodulin levels via adenoviral overexpression or treating with recombinant fibromodulin has been shown to reduce scar formation in rabbit, mouse, and red Duroc pig wounds [ 153 – 156 ] . Based on these studies, a fibromodulin-based peptide has been developed and is currently being tested in clinical trials [ 157 ] .…”