Transplantation of Ngn2-expressing human neural stem/progenitor cells into hypoxic-ischemic injured neonatal mouse brain

Abstract

Neonatal hypoxic–ischemic (HI) brain injury represents a major cause of cerebral palsy, developmental delay, epilepsy, and even death. Stem cell transplantation offers new treatment hope, but significant questions remain regarding how grafted cells exert effects. HI brain spontaneously undergoes reinnervation and rewiring of surviving neurons after injury and this is widely known as the innate repair capacity of the brain. Here, we demonstrate that adenovirus-mediated overexpression of neurogenin 2 (Ngn2) of human neural stem/progenitor cells (hNSPCs), which directly controls neurogenesis in the embryonic cerebral cortex, and transplantation into mice with HI brain injury, enhances functional recovery, host cell survival, and innate neuroplasticity after HI brain injury. Transplanted Ngn2-expressing hNSPCs differentiated into mostly neurons, and we suggest that these effects are mediated by the increase of the Ngn2-expressing hNSPCs-secreted factor neurotrophin 3 during hNSPCs neurogenesis. We also carefully propose the possibility that Ngn2-expressing hNSPCs may form synapses with other surviving neuron in peri-infarcted areas based on our observation that Ngn2-expressing hNSPCs expressed synaptophysin and growth cone. Our results are the first evidence that grafted hNSPCs with neural induction could have play a bifunctional role in that they replace lost cells and secrete neurotrophic factors to promote survival and connectivity.