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.
Highlights
Cutaneous wounds, acquired from surgery or trauma, can cause pathologic scarring with significant functional and psychological sequelae
FMOD significantly optimizes adult cutaneous wound healing Previously, we reported that wounds in the adult Fmod−/− mouse healed with increased scar formation, delayed wound closure, and reduced angiogenesis, which could be partially rescued by exogenous FMOD administration.[19,21]
Using an adult rat wound healing model, we demonstrated that exogenous FMOD significantly reduced scar size when compared with phosphate-buffered saline (PBS) control samples as evidenced by Picrosirius red (PSR) staining-coupled polarized light microscopy (PLM) (Figure 1a and b)
Summary
Cutaneous wounds, acquired from surgery or trauma, can cause pathologic scarring with significant functional and psychological sequelae. These pathologies cost the global healthcare system over $8.6 billion and affect 100 million patients annually.[1,2]. Transgenic mice studies reveal that simple TGFβ1 blockade does not promote ideal wound healing, and instead, TGFβ1-deficient mice die from overwhelming systemic inflammation within 3–4 weeks after their birth.[12] When crossed with severe combined immunodeficiency mice, TGFβ1-deficient mice survive but exhibit impaired granulation tissue formation and delayed cutaneous wound repair.[13] inducible fibroblast lineage-specific type II TGFβ receptorknockout mice demonstrate severely impaired fibroblast migration, myofibroblast development, and myofibroblast function, which leads to deficient granulation tissue formation and defective wound contraction.[14] These results indicate that TGFβ1 signaling has multiple roles in the wound healing process, and as such, non-specific TGFβ-blockade is detrimental to cutaneous repair
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