Colin Jamora, Ph.D.
Research Statement
The skin is a powerful model system to study organ development and regeneration. As one of the few organs in mammals that undergo continual regeneration, stem cells in the skin are consistently forced to balance the need to renew itself and maintain a pool of progenitor cells with the requirement to differentiate to reconstruct a tissue that turns over every few weeks.
We have two areas of focus dealing with the regulation of stem cell proliferation and differentiation in the epidermis. One project focuses on the question of how does the proliferating stem/progenitor cell decide when to exit the cell cycle and enter the terminal differentiation program to form the stratified epidermis. We have discovered that a protein known as E-cadherin can regulate when a keratinocyte differentiates. This is surprising given that E-cadherin has classically been studies in the context of intercellular adhesion at the surface of cells and the mechanics of tissue homeostasis rather than cell fate specification. Our current efforts are dedicated towards elucidating the intracellular signaling cascade linking E-cadherin at the cell surface with the reprogramming of the cell through alterations in gene expression.
The second project on epidermal stem cells focuses on the signals that regulate their proliferation rate during wound repair. We have been investigating a novel role for the protein caspase-8 in surveying epidermal integrity. Caspase-8 is a well known mediator of apoptosis and would be predicted to be involved in the normal turnover of the epidermal cells. However, conditional deletion of this gene in the epidermis demonstrated that caspase-8 is dispensible for the death of skin cells and instead revealed that it coordinates stem cell proliferation, keratinocyte migration and inflammation in the skin during the wound healing process. We are using a combination of mutant mouse models to determine caspase-8’s contribution to tissue regeneration and repair along with cultured keratinocytes to delineate the signaling pathways that are regulated by caspase-8.
Another major effort over the last few years has been focused on how the multipotent ectodermal cells that give rise to the epidermis instead develop into a hair follicle. The particular stage of hair development that we concentrate on is the formation of a hair bud – a small group of cells that protrude from a planar sheet of epithelial cells. This process of budding morphogenesis is a common theme in the development of a variety of organs such as the lungs, liver, and pancreas and we employ the hair as a model to understand the fundamental properties of organogenesis. Moreover, the invasion of the hair bud from the epithelial compartment of the skin into the underlying mesenchymal compartment resembles the metastasis of tumor cells and can inform us of the mechanism by which cancer cells spread.