Targeting of hematopoietic stem cells to the CNS and differentiation into glia and neurons

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Recent studies demonstrate the migration of bone marrow derived cells into the central nervous system (CNS) past the blood-brain barrier and their differentiation into microglia, astrocytes and possibly neurons. These reports suggest the possibility that hematopoietic stem cells may be used, first, to replace brain cells lost following neurodegeneration and, second, as a natural vehicle to migrate through the blood-brain barrier into the CNS. This project will assess the migration and differentiation of genetically engineered hematopoietic stem cells in mice. Hematopoietic stem cells (lin-, c-kit+, sca-1+), isolated by flow cytometry from mice expressing green fluorescenent protein (GFP) under the ß-actin promotor, will be primed for a short time period with neural differentiation factors (e.g. FGF-2, EGF) and retrovirally transduced to express chemokine receptors (e.g. CX3CR1), which bind CNS-derived chemokines. The GFP-marked cells will then be applied intravenously into mice and later analyzed in the brain tissue by immunohistochemistry, flow cytometry and electrophysiology. If successful, this technique will provide a method for targeting of hematopoietic stem cells to the CNS and their possible differentiation in resident brain cells including glial cells and neurons.