Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis

Abstract

The Wnt/β-catenin pathway has been implicated in hair follicle development and hair regeneration in adults. We discovered that CXXC-type zinc finger protein 5 (CXXC5) is a negative regulator of the Wnt/β-catenin pathway involved in hair regrowth and wound-induced hair follicle neogenesis via an interaction with Dishevelled. CXXC5 was upregulated in miniaturized hair follicles and arrector pili muscles in human balding scalps. The inhibitory effects of CXXC5 on alkaline phosphatase activity and cell proliferation were demonstrated using human hair follicle dermal papilla cells. Moreover, CXXC5 mice displayed accelerated hair regrowth, and treatment with valproic acid, a glycogen synthase kinase 3β inhibitor that activates the Wnt/β-catenin pathway, further induced hair regrowth in the CXXC5 mice. Disrupting the CXXC5-Dishevelled interaction with a competitor peptide activated the Wnt/β-catenin pathway and accelerated hair regrowth and wound-induced hair follicle neogenesis. Overall, these findings suggest that the CXXC5-Dishevelled interaction is a potential target for the treatment of hair loss.

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

“…WIHN is dependent on epidermal Wnt/β-catenin signaling. WIHN can also be promoted by direct modulation of Wnt signaling components such as Wnt ligands Wnt7a [92] and Wls [93], or indirectly through its negative regulator CXXC-type zinc finger protein 5 (CXXC5) [94], or through an external stimulus triggering Wnt activation, such as FGF9 released from dermal γδ T cells [95] or TNF released from wound-infiltrating macrophages [96]. In addition, it has been shown that WIHN requires transient epithelial Msx2 expression [97] and can be inhibited by prostaglandin D2 through the receptor Gpr44 [98].…”

Review of Hair Follicle Dermal Papilla cells asin vitroscreening model for hair growth

“…Peptides and some growth factors have also shown inhibitory effects on DPCs. In addition, certain other agents have exerted inhibition of DPCs activity in vitro .…”

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

“…Aberrant Wnt signaling has been found to be associated with hair loss (alopecia) and anabolic osteoporosis. A previous study demonstrated that expression of CXXC5 is upregulated and is inversely correlated with that of β‐catenin in both haired and bald individuals . In mice, CXXC5 knockout or competitive peptide‐mediated disruption of the CXXC5‐Dvl interaction restores Wnt signaling and accelerates hair regrowth and wound‐induced hair follicle neogenesis .…”

“…A previous study demonstrated that expression of CXXC5 is upregulated and is inversely correlated with that of β‐catenin in both haired and bald individuals . In mice, CXXC5 knockout or competitive peptide‐mediated disruption of the CXXC5‐Dvl interaction restores Wnt signaling and accelerates hair regrowth and wound‐induced hair follicle neogenesis . Similarly, targeting the CXXC5‐Dvl interaction with small molecules has been suggested as a new therapeutic approach for the treatment of anabolic osteoporosis …”

“…85 In mice, CXXC5 knockout or competitive peptide-mediated disruption of the CXXC5-Dvl interaction restores Wnt signaling and accelerates hair regrowth and wound-induced hair follicle neogenesis. 85 Similarly, targeting the CXXC5-Dvl interaction with small molecules has been suggested as a new therapeutic approach for the treatment of anabolic osteoporosis. 86 First, although CXXC5 is capable of associating with unmethylated CpG islands via its CXXC domain and regulating the expression of certain genes, the specific genomic sites at which CXXC5 binds to in a given cell type or context remain to be determined.…”