Stem cells exist in most if not all somatic tissues and are responsible for the generation of tissues and organ systems during embryonic and fetal development and for their maintenance and repair in adult life. The unique capacity for self-renewal and extended proliferation establishes tissue stem cells as unique targets for graft engineering, tissue regeneration and for gene therapy. There is rapidly increasing evidence that stem cells from one adult tissue can contribute to the regeneration of an unrelated tissue or organ. In accord with these observations, recent studies from this laboratory have show that epidermal cells in adult mouse skin can contribute to the regeneration of the hematopoietic (blood forming) system following their intravenous administration into irradiated recipient mice. Thus it appears that the developmental potential of somatic stem cells is inherently plastic. The external signals that control stem cell fate collectively make up the stem cell microenvironment. The apparent retention by adult somatic stem cells of a broad developmental potential suggests that signals provided by the local microenvironment may mask their pluripotentiality. Accordingly, removal of stem cells from their normal microenvironmentment and transplantation into the niche of a second, unrelated tissue may result in the acquisition by that stem cell population of the developmental fate of the recipient tissue. This application therefore seeks to investigate the mechanisms associated with the derivation of hematopoietic tissue from skin. This will include identification of the cells in the skin which can adopt a hematopoietic fate and a quantitative assessment of their efficacy as blood forming cells. Lastly we will examine whether the development of hematopoietic tissue from skin cells is dependent upon the induction of expression in these cells of SCL, a transcription factor with a pivotal role in specifying the fate of hematopoietic stem cells; and whether, having acquired a hematopoietic fate in reprogrammed cells can revert to their original tissue of origin.
