George Cotsarelis, M.D.
Associate Professor, Dept of Dermatology

Developmental, Stem Cell and Regenerative Biology Program

University of Pennsylvania, BA
(Bio Basis of Behavior ) 1983

University of Pennsylvania, MD 1987

Research Interests

• Cutaneous stem cells, hair follicle biology, alopecia, wound healing, skin regeneration

Key words: stem cells, regeneration, hair, alopecia, Fgf, Egf, Klf5, Wnts, transgenic mice.

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Description of Research

My lab focuses on studying epithelial stem cells in the hair follicle bulge. I originally discovered the location of stem cells in the bulge area of the hair follicle as a postdoctoral fellow (Cell, 1990). Since then, we developed transgenic mouse models, based on a keratin (K15) promoter that we cloned, for isolating and characterizing these cells. Using K15CrePR;R26R mice, we first demonstrated through genetic lineage analysis that bulge cells give rise to the seven types of epithelial lineages in the new lower follicle that forms at the onset of each hair follicle cycle. This mouse has served as a powerful model for studying the role of hair follicle stem cells in wound healing, carcinogenesis and skin regeneration. Using the model, we showed that hair follicle stem cells contribute approximately 30% of the new cells in a reepithelialized cutaneous wound. We are now studying the response of these cells to different types of wounds.

By driving expression of the suicide gene, thymidine kinase, to the bulge cells using the keratin 15 promoter, we demonstrated that bulge cells are necessary for follicle viability but that they do not contribute to homeostasis of overlying epidermis. This mouse serves as a model for cicatricial types of alopecia, which result in scarring and permanent loss of follicles.

We developed K15-EGFP transgenic mice and isolated hair follicle stem cells from adult mice. We first showed that isolated bulge cells gave rise to new hair follicles when mixed with dermal cells and injected into immunodeficient mice. These findings have implications on tissue engineering approaches for treating alopecia, wounds and other degenerative skin conditions.

Molecular characterization of the isolated hair follicle stem cells has led us to pursue the role of several candidate genes as important for maintaining the stem cell phenotype. We are studying the role of Fgfs and other growth and transcription factors in determining the quiescent and undifferentiated state of hair follicle stem cells. We are interested in genes that can convert non-stem cells into a stem-like state.

Most recently, we developed a model for skin regeneration in which hair follicles with associated stem cell populations are re-formed following wounding in mice. The new follicles form de novo and function normally. Intriguingly, they do not arise from preexisting hair follicle stem cells, but rather from non-bulge basal keratinocytes. Our research focuses on understanding the molecular signals involved in the transition of epidermal cells to hair follicle stem cells.

Recent Publications

Cotsarelis, G, and Millar, S. Towards a molecular understanding of hair loss and its treatment. Trends in Molecular Medicine 7: 293-301, 2001.

*Morris, R., *Liu, Y., Marles, L., Yang, Z., Trempus, C., Li, S., Lin, J., Sawicki, J., Cotsarelis, G. Capturing and profiling hair follicle stem cells. Nature Biotechnology 22:411-417, 2004. *equal contributors

*Ito, M., *Liu, Y., Yang, Z., Nguyen, J., Liang, F., Morris, R., Cotsarelis, G. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Medicine 11: 1351-1354, 2005. *equal contributors

Cotsarelis, G. Epithelial stem cells: a folliculocentric view. J Invest Dermatol. 126:1459-1468, 2006.

Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., Millar, S.E. Cotsarelis, G. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 447: 316-321, 2007.

Lab

Rotation Projects

1. Role of EGF/EGFr in wound healing and skin regeneration.
2. Function of Keratin 15 in skin biology (analysis of K15 knockout mouse)
3. Role of FGFs in wound healing and skin regeneration.
4. Use of adult skin stem cells to tissue engineer human skin and hair follicles.

Lab personnel:

Mayumi Ito, Ph.D. Postdoctoral Fellow
Luis Garza, M.D., Ph.D. Instructor/Postdoctoral Fellow
Peggy Myung M.D., Ph.D. Postdoctoral Fellow
Ohsang Kwon, M.D., Ph.D. Visiting Scientist
Steven Prouty, Ph.D. Visiting scientist
Zaixin Yang, M.D. Research Specialist
Rita Schmidt Undergraduate Independent Study Student
Hans Blatt, Undergraduate Work Study Student