Oral communication, PS3 / C36

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Protective effect of Kit signaling for melanocyte stem cells against radiation-induced genotoxic stress

SPEAKER H. Aoki #whois submiter ?
AUTHOR(s) H. Aoki, T. Kunisada

BACKGROUND: Radiation-induced hair graying is caused by irreversible defects in the self-renewal and/or development of follicular melanocyte stem cells (MSCs) in the hair follicles. X-ray damaged melanocyte stem cells seemed to take the fate of ectopically pigmented melanocytes in the bulge regions of hair follicles in vivo. Kit signaling is an essential growth and differentiation signaling pathway for various cell lineages including melanocytes and its radioprotective effects have been shown in hematopoietic cells. OBJECTIVE: To investigate whether Kit signaling exerts a radioprotective effect for melanocytes, we investigated the radioprotective function of Kit signaling in melanocytes in vivo. METHODS: According to the telogen-hair plucking method (Potten, 1970), one day after plucking the hair on the dorsal skin, the mice were irradiated at 7–8 weeks of age (Argyris and Chase, 1960). Whole-body X-ray radiation (IR) was performed using a Hitachi MBR-1520 (Hitachi Medical) operating at 50 kV or 150 kV, 20 mA with a 2.0 mm Al filter and a dose rate of 0.4 Gy/min as previously reported (Inomata et al., 2009). 6, 24 hours or 1 week after irradiation, the skins were analyzed by immunohistochemistry. RESULTS: Various loss-of-function mutations of Kit facilitate radiation-induced hair graying. The extreme possibility that changes in the numbers of MSCs in vivo were the cause of the radioprotective effect of Kit signaling observed was excluded by demonstrating the nearly constant numbers of MSCs in the mice used in our experiments. The X-ray doses used did not show a systemic lethal effect, indicating that the in vivo radiosensitivity of Kit mutants is mainly caused by the damaged MSC population. In contrast, transgenic mice expressing the ligand for Kit (Kitl) in the epidermis have significantly reduced levels of radiation-induced hair graying. We also observed a reduced frequency of double strand breaks measured by phosphorylated H2AX staining which corresponded to the increased Kit signaling level. The prominent radioresistance of MSCs observed in hk14-Kitl transgenic animals. Endothelin 3, another growth and differentiation factor for melanocytes, showed a lesser radioprotective effect compared with Kitl. CONCLUSION: By comparing hair graying at various Kit signaling levels following exposure to IR, we demonstrate a significant in vivo radioprotective role of Kit signaling in the regeneration of melanocytes in hair follicles.



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