Altering Fate of Hematopoietic and Neural Stem Cells

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DESCRIPTION (provided by applicant): The notion of stem cell plasticity has been recently supported by numerous examples of so-called tissue specific stem calls being coaxed into other tissue phenotypes. Altering fate of tissue-specific stem cells, inducing transdifferentiation, has been reported in many different bioassays, using a variety of cell culture and in vivo conditions and manipulations, without a systematic and direct comparison of different stem cell populations from different tissues in the same study. This proposal sets up a "head-to-head" comparison of transdifferentiation abilities of hematopoietic and neuropoietic stem cells in three sets of experiments that will establish the ability to alter the fate of hematopoietic and neuropoietic stem cells In vitro, embryonic and adult mouse in vivo studies will test hypotheses related to epigenetic factors that control the choice of fate as well as terminal differentiation of stem cells isolated from hematopoietic and neuropoietic structures Their ability to transdifferentiate, both in vitro and in vivo, will be evaluated using sensitive phenotypic and functional analyses, to confirm their full conversion and integration into their new host environments Specific Aim 1 will determine whether a candidate stem cell from the postnatal and adult mouse brain in fact exhibits true stem cell behaviors, looking at established attributes of hematopoietic stem cells including self-renewal and long-term clonal, multilineage reconstitution. This starting population will be sorted and enriched using specific surface antigens in order to determine the affects of culturing on developmental potential. Specific Aim 2 will look at the ability of hematopoietic stem cells to respond to neural cues in vitro and in vivo, by contributing functional cells that integrate within the developing, and repopulating adult nervous system Finally, Aim 3 will test the hypothesis that neural stem cells are plastic enough to respond to hematopoietic cues, following their transplantation into embryoid bodies, fetal mice, and radiation-ablated bone marrow The "head-to-head" assay systems to be used here will determine the potential usefulness of transdifferentiation approaches for establishing new cell therapeutics for many different human diseases, including cell loss as well as hyperplasia in a variety of blood and brain disorders Before we can understand the potential of blood ceils to become brain cells, a profound example of transdifferentiation that offers numerous alternative approaches to current cell replacement therapies, it is necessary to establish sternness of starting cell populations, and also understand factors involved in blood/brain stem cell proliferation, commitment to fate, and differentiation.