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Elaine Fuchs,
Ph.D.
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.
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