STUDIES OF ADULT BRAIN NEUROPOIESIS

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DESCRIPTION (provided by applicant): Homing, maintenance, and integration of stem cells in the central nervous system are rather new topics in emerging fields of neuropoiesis and regeneration neurobiology. The notion of stem cell plasticity has been advanced by different examples of so-called tissue specific stem cells being coaxed into other tissue phenotypes. This 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. This proposal will compare homing, stem cell renewal, fate control and differentiation under neuralizing conditions in a persistently neurogenic (or "neuropoietic") region of the adult rodent brain - the subependymal zone (SEZ) and its rostral migratory stream (RMS) that is involved in continual repopulation of forebrain structures including the olfactory bulb. Three specific aims are proposed that will evaluate two candidate stem cell populations from brain (multipotent astrocytic stem cells, or "NSC" for neural stem cells) and blood ("HSC", hematopoietic stem cells) using in vivo and in vitro bridging bioassays. Specific Aim 1 will test the hypothesis that particular extracellular matrix molecules (tenascin-C and chondroitin sulfate proteoglycan), a candidate integrin receptor, cell surface molecules (CD 15 and CD9), and a chemokine and its receptor (SDF-1/CXCR4) are expressed by these cells and the SEZ/RMS to facilitate stem cell homing, maintenance and integration. Aim 2 will further test this, via studying the possible actions of these molecules in vivo following transplantation of NSC and HSC, using knockout animals and function blocking antibodies to these candidate homing/integration factors. Finally, Aim 3 will test the hypothesis that NSC and HSC can functionally integrate within forebrain neurogenic structures, using sensitive morphological and electrophysiological analyses of tissue explants - stem cell coplants. Before we can understand the potential of blood cells to become brain cells, a profound example of transdifferentiation that offers numerous alternative approaches to current cell replacement therapies, it is necessary to understand degrees of stemness of starting cell populations, and also elucidate factors involved in stem cell homing, maintenance, and integration to and within damaged CNS circuits. The studies proposed here also provide insights into long term culturing and integration of neuropoietic and hematopoietic cells, with an eye toward the development of therapeutics for a variety of brain and blood diseases.