Stroke is a leading cause of disability in the United States, yet it has limited treatment options. Stem cell therapy offers a novel therapeutic strategy for stroke, and several clinical trials are underway. We are investigating the mechanisms by which stem cells enhance recovery in preclinical animal models of stroke. In this award we have found that within a week of transplanting our stem cells into the stroke-injured brain they modify brain activity in specific cortical layers. Effects on inflammation are also evident. Using genetic manipulation of our stem cells, and specialized bioinformatics tools, we have identified what the transplanted stem cells express in the stroke-injured brain. We are now in a position to elucidate how the stem cells communicate with the brain to elicit recovery after stroke injury.