Hedgehog signaling is essential for normal wound healing

Abstract

The hedgehog family of morphogens (sonic [Shh], Indian, and desert hedgehog) are central regulators of embryologic growth and tissue patterning. Although recent work implicates Shh in postnatal tissue repair and development, conclusive evidence is lacking. Here, we demonstrated the importance of Shh in wound repair, by examining the effects of cyclopamine, a specific inhibitor of the Shh signaling cascade, on tissue repair. Using a murine-splinted excisional wound model, which attenuates wound contraction in this loose-skinned rodent, we established that, by all measures (wound closure, epithelialization, granulation formation, vascularity, and proliferation), wound healing was profoundly impaired when Shh signaling was disrupted. Because embryonic disruption of Shh is associated with distinct phenotypic defects, our findings invite investigation of the potential role of Shh signaling under postnatal conditions associated with disregulated wound healing.

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

“…68 Endogenous Shh is a downstream target of hypoxia-induced factor-1a 46 and it promotes adaptive neovascularization in the setting of pathologic tissue ischemia. 69 After exposure to Shh, resident mesenchymal cells regulate a variety of genes with distinct angiogenic functions, 46 including multiple isoforms of VEGF, which promote blood vessel formation, and angiopoietins, which promote vessel branching, stability, and maturity. 70 By a mechanism that appears to involve noncanonical Rho signaling rather than canonical Gli-mediated signaling, Shh also directly stimulates ECs to migrate into the wound bed 52 and encourages their differentiation into tubules.…”

The wound healing, chronic fibrosis, and cancer progression triad

“…Gli-1 appears to be the most abundant Hhactivated transcription factor, while Sonic Hh (SHh) is the better characterized ligand in the signaling pathway (58). SHh signaling is essential for wound healing as demonstrated by the inhibitory effect imparted by the topical application of a cyclopamine, a well-characterized inhibitor of smoothened, at all stages of the wound healing process (200). However, SHh signaling has also been shown to promote fibrosis in several organs such as lung, liver, and skin (157).…”

Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation

“…Hh signaling is relatively silent during homeostasis but reactivates during several adult regenerative processes, participates in neovascularization (10,(11)(12)(13)(14), and in fracture healing (10)(11)(12)(13)(14)(15).…”

“…Among the three human Hh genes (Sonic, Indian, and Desert Hedgehog), Sonic Hedgehog (Shh) is the most expressed, is essential for endothelial tube formation during vascular embryonic development (16), neovascularization upon adult trauma, and wound healing (12)(13)(14)(17)(18).…”