There are approximately 4 million stroke survivors in the United States. Little attention has been directed to replacing lost neurons and brain tissue after a cerebral infarct. Since the time window for its application is relatively broad, cell replacement therapy remains a potential treatment option for stroke survivors. There is increasing evidence that the differentiation potential of bone marrow-derived cells is not fixed but strongly influenced by environmental cues. Recent studies show that bone marrow-derived stem cells differentiate into microglia, astrocytes, and neurons. Brain injury such as stroke may enhance this differentiation potential. The inflammatory response associated with stroke, while harmful in some ways, may also be reparative and serve to supply the brain with a reservoir of progenitor cells. Our central hypothesis is that after focal cerebral ischemia, a population of bone marrow-derived stem cells serve a regenerative function and differentiate into cerebral endothelial cells, astrocytes and "functioning" neurons. Our specific aims are: 1.) Determine if bone marrow-derived stem cells serve as progenitor cells for cerebral endothelial cells and contribute to the neovasculanzation that occurs after a focal cerebral ischemic insult; 2.) Determine if bone marrow-derived stem cells transdifferentiate into functioning neurons after focal cerebral ischemia; 3.) Determine if intravenously administered bone marrow derived stem cells differentiate into endothelial cells and/or functioning neurons in the ischemic brain. In this proposal we will use a radiation chimera in which Green Fluorescent Protein (GFP) and Y chromosome-tagged marrow will be transplanted into irradiated female mice. Later these mice will undergo suture occlusion of the middle cerebral artery and the fate of the tagged marrow cells that enter the brain will determined by double-label immunocytochemistry. In some experiments, GFP-expressing and Y chromosome tagged bone marrow derived cells will be administered intravenously into mice after a stroke. Using brain slices we will determine if cells which express neuronal markers have electrophysiological and functional characteristics of neurons (e.g. membrane excitability; glutamate and GABA-mediated synaptic events
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