Effect of adenovirus-mediated expression of Sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia

Background: The Sonic hedgehog (Shh) gene is involved in the initiation of hair growth. We have shown that localized, transient, enhanced expression of the Shh gene in mouse skin mediated by an adenovirus (AdShh) vector accelerates initiation of the anagen (i.e., growth) phase of hair follicle development. Because hair regrowth in chemotherapy-induced alopecia is associated with follicle cell proliferation and active melanogenesis similar to that observed in the anagen phase of normal hair growth, we examined whether AdShh-mediated Shh expression would accelerate hair regrowth in the skin of mice with chemotherapy-induced alopecia. Methods: After establishment of cyclophosphamide-induced alopecia, in either 3- or 7-week-old mice, AdShh or a control vector (AdNull) was delivered to dorsal skin by intradermal injection. Hair regrowth and melanogenesis were assessed by histology and gross morphology. Fisher's exact test was used to compare differences in outcomes between AdShh-treated and control (AdNull-treated or not injected with any vector [naive]) mice. All statistical tests were two-sided. Results: Northern blot analysis confirmed enhanced Shh expression after AdShh administration in 7-week-old mice. Two weeks after AdShh administration, the injection site (all of five mice) showed large, anagen-phase hair follicles with a normal distribution of melanin. In contrast, both skin treated with AdNull (all of five mice) and skin from naive mice (all of five mice) showed dystrophic hair follicles with irregular distribution of melanin (P < .001 in both comparisons). Gross morphologic observations confirmed that AdShh-treated mice, but not naive mice or AdNull-treated mice, showed skin darkening at the injection site indicative of entry into anagen phase (P < .001 in both comparisons). AdShh treatment of 3-week-old mice with cyclophosphamide-induced alopecia was followed by accelerated hair follicle recovery (19 of 22 mice); such recovery was not observed at this rate in AdNull-treated or naive skin (P < .001 for both comparisons). Conclusion: Localized, transient, enhanced expression of Shh gene in skin, mediated by an adenovirus vector, might be a future strategy to accelerate hair follicle regrowth after chemotherapy-induced alopecia.