Award Lecture 2006
Elaine Fuchs, PhD
Howard Hughes Medical Institute, The Rockefeller University, NY, NY 10021
To be Presented April 5, 2006, ASBMB Annual Meeting, San Francisco, CA,
2006 FASEB Experimental Biology Symposium
"Stem Cells and Their Lineages in Skin"
Stem cells have the capacity to self-renew and to differentiate along multiple lineages. In adult tissues, they typically reside in a protected niche and are used only sparingly to maintain homeostasis. In response to injury, stem cells are mobilized to exit their niche, proliferate and differentiate to repair damaged tissue. The ability of Stem cells to maintain their growth and differentiation inhibited state while in the niche relies upon a balance of intrinsic and extrinsic factors. The niche must then be stimulated in order for stem cells to become mobilized and exit their specialized microenvironment. A central issue in stem cell biology is the relationship between stem cells and their niche, and how these interactions may be important in self-renewal and activation of stem cells. The skin is an excellent model system to explore these processes at a molecular level. In postnatal life, the skin sets aside reservoirs of quiescent multipotent epithelial stem cells in the upper portion of each hair follicle. In response to a wound stimulus, these stem cells can become activated and mobilized to move upward to repair the epidermis. In response to a periodic specialized mesenchymal signal, a few stem cells become activated and mobilized to exit the niche to produce rapidly dividing progeny that differentiate to produce the new hair follicle and initiate a round of hair growth. This growth phase is limited and is eventually followed by a destructive and resting phase, leading to the loss of the old hair. A new mesenchymal signal then starts the process anew.
To understand the complex but fascinating process by which multipotent stem cells of the skin respond to these stimuli, change their transcriptional program and choose a specific cell fate, we have developed novel approaches to fluorescently tag and isolate the stem cells in their quiescent and activated states, as well as the specialized mesenchymal cells that signal to the stem cells to make a hair follicle. Transcriptional profiling, biochemical studies and functional analyses have allowed us to dissect out some of the key steps in stem cell lineage commitment. Questions that we are addressing include: 1) How does the microenvironment establish a niche architecture that renders directionality to the exit of cells from the niche and permits replenishment of stem cells within the niche? 2) How do follicle stem cells change their program of gene expression as they are activated and how are different lineages fated? By addressing these questions, we hope to learn how external stimuli elicit transcriptional, cytoskeletal and adhesive changes that can orchestrate the assembly of cells into a tissue. Our ultimate goal is to link the basic biology of our research to issues of human medicine.