Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis.
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.


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.
Zhou
Jia-xi
JX
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
Jia
Li-wei
LW
Liu
Wei-min
WM
Miao
Cheng-lin
CL
Liu
Shuang
S
Cao
Yu-jing
YJ
Duan
En-kui
EK
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D004817:Epidermis / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013234:Stem Cells / Q000166:cytology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D004815:Epidermal Growth Factor; C000541:cyclopamine