Stem and precursor cells have now been identified in the adult rodent and human brain, and there is a growing interest in manipulating these cells to proliferate and differentiate along particular lines that might favor their use in cell replacement therapies for neurological disease. Whereas most groups have studied these cells and their in vitro generation of neurospheres from the embryonic or early postnatal brain, our lab has focused on the presence and proliferation of stem/precursor cells in the adult brain - so called neuropoiesis . The presence of developmentally regulated cell adhesion and extracellular matrix (ECM) molecules on and around these cells in vivo in the subependymal zone, a region we have begun to refer to as brain marrow , suggests that manipulating the adhesive interactions of stem/precursor cells might enhance their proliferation and also offer a level of control over their differentiation into, e.g., particular types of neurons. This proposal is founded on the premise that in vitro ECM perturbation experiments, use of novel cell feeder layers, and transplantation experiments will afford the isolation and characterization of distinct types of adult brain stem/precursor cells, and at the same time help us direct the growth and differentiation of these cells into progenitors and fully differentiated cells (e.g. neurons) that are able to integrate into established and compromised neuronal circuitries. Tissue culture and brain grafting experiments will be performed using normal and ECM-deficient transgenic mice to: 1) prove that manipulating ECM molecules can lead to an ex vivo expansion of stem/precursor cell populations, and also restrict cell lineage; 2) test feeder layers derived from non-neural tissues to release growth factors and other molecules that help to discriminate and sustain the most primitive classes of stem/precursor cells for extended periods of time in culture to allow more extensive analyses of their self-renewal, proliferation and differentiation; and 3) use feeder layer and other growth- inducing substrates to prime stem/precursor cell populations from the adult brain to better survive and integrate as grafts into the adult brain. Thus, using novel culture approaches, and immunocytochemical and molecular analyses of cell phenotype and developmental genes expressed by adult brain stem/precursor cells, these studies will elucidate factors that may be crucial to the survival and growth of these potentially clinically important, resident cells of the mature human brain.
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