New Scholar Award in Aging
Steven Lyle, M.D., Ph.D.
Beth Israel Deaconess Medical Center, Harvard Medical School

Molecular and Cell Biology of Adult Epithelial Stem Cells

The skin undergoes significant structural and functional changes with aging, secondary to both intrinsic and environmental factors. The epidermis and dermis become thinner, lose their normal rete pattern, exhibit decreased elasticity and show a decreased number of melanocytes. The hair becomes finer and loses pigment. There is also a decreased epidermal turnover rate, a slower clearance of toxins and immune dysfunction. The most important consequences of these alterations include: higher risk for cancer, increased skin fragility, decreased wound healing and the less threatening but equally unwelcome cosmetic effects. The long-term homeostasis of skin, like all self-renewing tissues, is dependent on adult stem cells, and thus global changes evident within skin likely represent the functional status of the stem cells. Although some of the pathways involved in controlling stem cell fate are being elucidated, the molecular and cellular changes occurring within epithelial stem cells of skin during aging remain largely unexplored.

We previously identified a marker, cytokeratin 15 (K15), that defined a specific population of keratinocytes located within the hair follicle and determined that these K15-positive cells had the in vivo and in vitro properties of adult epithelial stem cells. Using the K15 stem cell marker, it appears that there are significant changes in the location and number of stem cells within murine and human skin as the organisms age, suggesting a correlation with age-related structural and functional changes.

Our overall goal is to characterize cellular pathways which are involved in maintaining two critical stem cell properties: 1) self-renewal, i.e. stem cells must remain as a permanent population of cells within the tissue throughout our lifetime, and 2) stem cells are activated to proliferate and produce differentiated cells in order to replenish the tissue. In order to further characterize the basic nature of stem cells, we have utilized subtraction-hybridization and expression array analysis to identify additional genes which are differentially expressed within the stem cells and not in their more differentiated daughter cells. We are currently employing in vitro cellular assays to characterize the biologic differences between the stem cells and their daughter transit-amplifying cells and are studying the function of differentially expressed genes in maintaining stem cell properties. We are also beginning to analyze the age-related changes in cell behavior and gene expression within the stem cells of murine and human skin and correlate them with the K15 stem cell marker and other physical properties of skin. These experiments should increase our understanding of the basic biology of adult epithelial stem cells, identify pathways which could be manipulated to preserve or enhance stem cell function and ultimately lead to the development of methods to mitigate or reverse the effects of aging on self-renewing tissues. 

Contact Dr. Lyle.