Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype

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.

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

“…On the contrary, one-time administration of FMOD at the surgical time markedly improved the visual scar appearance of normal red Duroc pig wounds, which were identical to wounds previously assessed in adult female Yorkshire pigs [6] 8 weeks post-injury ( Fig. S3A and B).…”

“…In our experiment, we demonstrated that acute TAC injections did not considerably improve the gross appearance of excessive-mechanical-loading porcine wounds ( Fig. 1A and B) as assessed by an adaption of the Visual Analogue Score [6] (VAS, Fig. S2), although TAC-treated normal wounds exhibited lower VAS ( Fig.…”

“…Meanwhile, confocal laser scanning microscopy (CLSM) demonstrated increased fractal dimension (F D ) and decreased lacunarity (L) values in FMOD-treated wounds compared to those of control groups (Fig. S4), indicating a finer texture in FMOD-treated wounds [6]. On the contrary, application of TAC only elevated F D values without reducing L values (Fig.…”

“…In particular, our previous studies revealed that FMOD has a unique mechanism of action to elicit a more 'foetal-like' pro-migratory and pro-contractility phenotype in adult dermal fibroblasts [6]. Essentially, FMOD reduces scar formation without diminishing the tensile strength in adult wound models such as mice, rats and even the Yorkshire pig, which has been shown to simulate normal human skin wound healing [6]. # Wenlu Jiang and Kang Ting contributed equally to this work.…”

CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells

“…It has been hypothesized that the pluripotent cell microenvironment plays important roles determining cell fate, as well as the maintenance and induction of pluripotency/multipotency (59). In support of this, early pioneering studies demonstrated the success- ing a fetal-like phenotype of adult dermal fibroblasts (70). FMOD is also a critical component for the maintenance of endogenous stem cell niches (71,72).…”