iPS-Interneuron Transplantation for Neural Repair after Stroke

Stroke is the leading cause of adult disability. Because of the aging population and increasing risk factors, such as diabetes, the prevalence of stroke is increasing in the US: currently there are more people living with stroke than with Alzheimer’s and Parkinson’s diseases combined. There is no therapy that promotes tissue repair and recovery in stroke. A major limitation to a neural repair therapy in stroke is that the circuitry of the brain is complex and poorly understood, and it is difficult to design a drug or cell therapy that can reconstitute this circuitry. The studies in this grant hypothesized that a stem cell therapy based on a cell type that normally migrates widely in the brain and integrates into brain circuits in development would be capable of doing the same after stroke, and repairing damaged brain circuits. This cell type is the interneuron, and is developed by differentiating human induced pluripotent stem cells (hiPS cells) using a combination of small molecules (3 protein inhibitors, or “3i”). The cell line is termed hiPS-3i cells. Transplantation of hiPS-3i cells into the stroke cavity produces behavioral recovery when done at two clinically relevant time points: a subacute time point after stroke (the first week) and a chronic time point after stroke, equivalent to months after stroke in human patients. The transplantation of hiPS-3i cells reduces tissue damage that occurs progressively over time after stroke, and reduces scarring and inflammation. These results identify a neural repair therapy for stroke, which can be delivered at times when stroke patients are out of the hospital from their acute stroke event, and which is effective at early and late time points in this disease.