Characterisation of Bipotential Epidermal Progenitors Derived from Human Sebaceous Gland: Contrasting Roles of c-Myc and -catenin

¹ Massachusetts General Hospital Center for Regenerative Medicine, 185 Cambridge Street, CPZN-4400, Boston, MA 02114, USA
² CR-UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE
³ Barts and The London Queen Mary's School of Medicine and Dentistry, Institute of Cell and Molecular Science, Centre for Cutaneous Research; Newark Street, London E1 2AT
⁴ Wellcome Trust Centre for Stem Cell Research, Tennis Court Road, Cambridge CB2 1QR
⁵ UMass Cancer Center Tissue Bank, Departments of Cancer Biology and Pathology, UMass Medical School, 364 Plantation Street, Worcester, MA 01605, USA
⁶ Departments of Dermatology and Immunology, Dessau Medical Center, 06847 Dessau, Germany
⁷ CR-UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE; Wellcome Trust Centre for Stem Cell Research, Tennis Court Road, Cambridge CB2 1QR

^* To whom correspondence should be addressed. E-mail: fiona.watt{at}cancer.org.uk.

	Abstract

It is currently believed that the epidermal sebaceous gland (SG) is maintained by unipotent stem cells that are replenished by multipotent stem cells in the hair follicle (HF) bulge. However, sebocytes can be induced by Myc activation in interfollicular epidermis (IFE), suggesting the existence of bipotential stem cells. We found that every SZ95 immortalised human sebocyte that underwent clonal growth in culture generated progeny that differentiated into both sebocytes and cells expressing involucrin and cornifin, markers of IFE and HF inner root sheath differentiation. The ability to generate involucrin positive cells was also observed in a new human sebocyte line, Seb-E6E7. SZ95 xenografts differentiated into SG and IFE but not HF. SZ95 cells that expressed involucrin had reduced Myc levels; however, this did not correlate with increased expression of the Myc repressor Blimp1, and Blimp1 expression did not distinguish cells undergoing SG, IFE or HF differentiation in vivo. Overexpression of Myc stimulated sebocyte differentiation, whereas overexpression of -catenin stimulated involucrin and cornifin expression. In transgenic mice simultaneous activation of Myc and -catenin revealed mutual antagonism: Myc blocked ectopic HF formation and -catenin reduced SG differentiation. Overexpression of the Myc target gene Indian Hedgehog did not promote sebocyte differentiation in culture and cyclopamine treatment, while reducing proliferation, did not block Myc induced sebocyte differentiation in vivo. Our studies provide evidence for a bipotential epidermal stem cell population in an in vitro model of human epidermal lineage selection, and highlight the importance of Myc as a regulator of sebocyte differentiation.

Key Words. epidermis, sebaceous glands, cell differentiation, myc oncogene, -catenin

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