Our laboratory is interested in elucidating the basic cellular and molecular mechanisms implicated in cell fate choice and stem cell activity within tissues. We use the mouse as a model system. An important focus is on the control of nuclear function and structure including transcriptional networks, chromatin structure and dynamics, and DNA replication. Understanding how progenitor and differentiated cells function in normal tissue morphogenesis and homeostasis will reveal how deregulation of their precise control of growth and differentiation can lead to diseased tissues and cancer.
Our laboratory focuses on adult stem cells and their interaction with their tissue of residence, and uses the mouse skin as a primary model system to address the general questions outlined above. Within the skin epithelia stem cells are thought to reside both in the outer epidermis and in a specialized area of the hair follicle called the bulge. The bulge is a stem cell niche thought to keep their potent resident cells in a differentiation and proliferation inhibited state. It allows external signals to selectively penetrate and instruct stem cells to migrate out and proliferate when they are needed: during the initiation of the hair follicle growth and in wounded, regenerating skin. The bulge area is marked by a profoundly quiescent population of cells, known to incorporate BrdU (bromodeoxyuridine) label in the newly synthesized DNA and retain this label preferentially relative to other cells in the skin, for extended periods of time during the animal adult life. These label retaining cells (LRCs) have been attributed stem cell potential for more than 20 years, not only in the hair follicle, but also in other tissues where they have been identified.
We have devised a novel technique to isolate LRCs from tissues based on their GFP retention. A pulse and chase with histone H2B fused with GFP, with expression regulated by the tetracycline inducible system, allowed us to label and isolate live LRCs from the hair follicle bulge. Using a genomic approach a large number of factors preferentially expressed in bulge cells were identified. A significant fraction of these factors were likely involved in the cross-talk between bulge cells and the surrounding environment, suggesting a possible role for LRCs in organizing the stem cell niche.