Hum. Reprod. Advance Access originally published online on March 29, 2006
Human Reproduction 2006 21(7):1698-1704; doi:10.1093/humrep/del086
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Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis
1 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences 2 Graduate School of the Chinese Academy of Sciences, Beijing, People’s Republic of China
3 To whom correspondence should be addressed at: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuanxilu, Beijing 100080, People’s Republic of China. E-mail: duane{at}ioz.ac.cn
* These authors contributed equally to this work.
BACKGROUND: The mammalian epidermis is maintained by the ongoing proliferation of a subpopulation of keratinocytes known as epidermal stem cells. Sonic hedgehog (Shh) can regulate morphogenesis of hair follicles and several types of skin cancer, but the effect of Shh on proliferation of human putative epidermal stem cells (HPESCs) is poorly understood. METHODS AND RESULTS: We first found that Shh, its receptors Patched1 (Ptc1) as well as Smoothened (Smo) and its downstream transcription factor Gli-1 were expressed in the basal layer of human fetal epidermis and freshly sorted HPESCs. Next, treatment of HPESCs with media conditioned by Shh-N-expressing cells promoted cell proliferation, whereas inhibition of Shh by cyclopamine, a specific inhibitor of Shh signalling, had an opposite effect. Interestingly, the mitogenic effect of epidermal growth factor (EGF) on HPESCs was efficiently abolished by cyclopamine. Finally, bone morphogenetic protein 4 (BMP-4), a potential downstream effector of Shh signalling, increased HPESC proliferation in a concentration-dependent manner. CONCLUSIONS: Shh is an important regulator of HPESC proliferation in the basal layer of human fetal epidermis and modulates the cell responsiveness to EGF, which will assist to unravel the mechanisms that regulate stem cell proliferation and neoplasia in the human epidermis.
Key words: BMP-4/EGF/human putative epidermal stem cells/sonic hedgehog
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