Valerie Horsley, Ph.D. B.S. Furman University 1998 Ph.D. Emory University 2003

			Proliferation in the skin. E-cadherin (green) marks cells of the epidermis and hair follicle. Ki67 (red) marks the highly proliferative cells.

Our lab studies the cellular and molecular mechanisms that control stem cell activity and function within epithelia, the tissues that line our internal organs and outer surfaces. We use the mouse as a genetic model system to study how adult stem cells within epithelial tissues maintain tissue homeostasis, wound healing and can contribute to cancer formation.

The primary epithelial tissue we use is the mammalian skin, which contains multiple stem cell populations and forms a complex tissue that protects our bodies from external pathogens and loss of internal bodily fluids. Mammalian skin is an excellent model to study stem cell biology because the epidermis and its appendages are in a constant state of regeneration, which is actively sustained by tissue stem cells. During development, a stratified epithelium forms from a single layer of cells which give rise to primarily three lineages: the epidermis, the hair follicle and its associated sebaceous gland. Following tissue formation, stem cell activity including proliferation and commitment to various cell lineages is crucial for the rapid turnover of the epidermis and the sebaceous gland as well as the cyclic regeneration of the hair follicle.

We are currently addressing the following topics:

» Control of cell proliferation in epithelial stem cells
» Regulation of cell fate choices within epithelial tissues

Figure 2. Differentiation in the epidermis. Keratin 10 (green) marks the differentiated cells of the epidermis while the basal, proliferative cells of the epidermis are marked by a6 integrin (red) expression.

			Figure 3. Stem cells of the hair follicle are marked by the transcription factor, NFATc1 and cell surface marker, CD34.

Stem Cell Proliferation. The hair follicle stem cells reside in the bulge region of the follicle and are characterized by their slow proliferation, which can be marked by their ability to retain DNA label such as bromodeoxyuridine, BrdU. We have identified a role for the calcium sensitive transcription factor, NFATc1 in the regulation of stem cell proliferation and activity in the hair follicle bulge. Inhibition of NFATc1 activity pharmacologically or via gene knockout results in precocious activation of the stem cells within the hair follicle and subsequent hair growth. We are identifying mechanisms that control NFATc1 activity in hair follicle stem cells. In addition, we will define further mechanisms that regulate stem cells within the skin and other epithelial cells.

Lineage formation. How do stem cells decide to which cellular fate to adopt? The skin is an excellent system to answer this basis question in developmental biology. The epithelium of the skin is composed of three primary lineages, the epidermis, hair follicle and sebaceous gland. We have identified multiple transcription factors that regulate lineage formation in the skin. One of these factors, Blimp1 is a transcriptional repressor that marks a unipotent stem cell population in the sebaceous gland. We are utilizing Blimp1 expression as a means to further understand how sebaceous glands form and contribute to human diseases. Future studies are planned to identify further mechanisms involved in lineage decisions in epithelial cells.

			Figure 4. Grafting of stem cells. Stem cells can be grafted onto donor skin and form hair follicles.

Selected Publications

V. Horsley, A. O. Aliprantis, L. Polak, L.H.Glimcher and E. Fuchs. (2008). NFATc1 balances quiescence and proliferation of skin stem cells. Cell. 132(2):299-310.

E. Fuchs and V. Horsley (2008) More than one way to skin... Genes and Development. 22(8): 976-85.

C. Blanpain, V. Horsley, and E. Fuchs. (2007) Epithelial Stem Cells: Turning over New Leaves. Cell. 128(3): 445-458.

V. Horsley, D. O'Carroll, R. Tooze, Y. Ohinata, M.Saitou, T. Obukhanych, M. Nussenzweig, A. Tarakhovsky and E. Fuchs. (2006). Blimp1 defines a novel progenitor population that governs cellular input to the sebaceous gland. Cell. 126(3):597-609.

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