Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats

Neural stem/progenitor cells (NSPCs) in subventricular zone (SVZ) produce new striatal neurons during several months after stroke, which may contribute to recovery. Intracerebral grafts of NSPCs can exert beneficial effects after stroke through neuronal replacement, trophic actions, neuroprotection, and modulation of inflammation. Here we have explored whether human fetal striatum-derived NSPC-grafts influence striatal neurogenesis and promote recovery in stroke-damaged brain. T cell-deficient rats were subjected to 1. h middle cerebral artery occlusion (MCAO). Human fetal NSPCs or vehicle were implanted into ipsilateral striatum 48. h after MCAO, animals were assessed behaviorally, and perfused at 6 or 14. weeks. Grafted human NSPCs survived in all rats, and a subpopulation had differentiated to neuroblasts or mature neurons at 6 and 14. weeks. Numbers of proliferating cells in SVZ and new migrating neuroblasts and mature neurons were higher, and numbers of activated microglia/macrophages were lower in the ischemic striatum of NSPC-grafted compared to vehicle-injected group both at 6 and 14. weeks. A fraction of grafted NSPCs projected axons from striatum to globus pallidus. The NSPC-grafted rats showed improved functional recovery in stepping and cylinder tests from 6 and 12. weeks, respectively. Our data show, for the first time, that intrastriatal implants of human fetal NSPCs exert a long-term enhancement of several steps of striatal neurogensis after stroke. The grafts also suppress striatal inflammation and ameliorate neurological deficits. Our findings support the idea that combination of NSPC transplantation and stimulation of neurogenesis from endogenous NSPCs may become a valuable strategy for functional restoration after stroke.