Molecular pathways regulating long-term maintenance of adult stem cells

Funding Details
Canadian Institutes of Health Research
  • Grant type: CIHR Fellowship
  • Years: 2011/12 to 2014/15
  • Total Funding: $131,667
Keywords
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Project Summary

Increasing evidence indicates that tissue repair and regeneration are mediated, at least in part, by adult stem cells, and that the negative effects of aging are due to reduced function of these stem cell populations. However, the molecular factors that promote maintenance and longevity of adult stem cells and, thus, the longevity of tissues are largely unknown. In this regard, the Miller laboratory previously identified and characterized an adult stem cell from the skin that they called SKPs for Skin-derived Precursors, which had striking similarities to stem cells identified in a particular region of the brain. Importantly, the Miller lab recently demonstrated that SKPs derive from a sox2-positive endogenous dermal stem cell, the first such to be identified, that apparently serves to maintain and repair the dermis layer of the skin. The Miller lab also recently started to identify particular molecular pathways that are responsible for maintenance of endogenous SKPs; in particular, two proteins of interest were identified, called TAp63 and sox2. Specifically, mice lacking TAp63 displayed aberrant wound-healing and premature skin aging, coincident with enhanced SKPs senescence, and, in initial studies sox2+/- mice displayed decreased hair follicle morphogenesis and aberrant wound-healing. In other words, the TAp63 and sox2 are proteins that help to maintain the SKP cell population as aging progresses. I have therefore hypothesized that TAp63 and sox2 function to maintain dermal stem cells for the lifetime of the animal, and to thereby promote tissue repair and prevent tissue aging. I will test this hypothesis using mice with genetic alterations to specific groups of skin cells to identify the exact role of the proteins TAp63 and sox2 in those cell types. The findings of this proposed research will improve our understanding of stem cells and how they can be effectively used in regenerative medicine and may lead to improved health of Canadians.