Neurotrophy and immunomodulation of induced neural stem cell grafts in a mouse model of closed head injury

Abstract

Closed head injury (CHI) usually results in severe and permanent neurological impairments, which are caused by several intertwined phenomena, such as cerebral edema, blood-brain barrier (BBB) disruption, neuronal loss, astroglial scarring and inflammation. We previously reported that induced neural stem cells (iNSCs), similar to neural stem cells (NSCs), can accelerate neurological recovery in vivo and produce neurotrophic factors in vitro. However, the effects of iNSC neurotrophy following CHI were not determined. Moreover, whether iNSCs have immunomodulatory properties is unknown. Mouse models of CHI were established using a standardized weight-drop device and assessed by neurological severity score (NSS). Although these models fail to mimic the complete spectrum of human CHI, they reproduce impairment in neurological function observed in clinical patients. Syngeneic iNSCs or NSCs were separately transplanted into the brains of CHI mice at 12h after CHI. Neurological impairment post-CHI was evaluated by several tests. Animals were sacrificed for morphological and molecular biological analyses. We discovered that iNSC administration promoted neurological functional recovery in CHI mice and reduced cerebral edema, BBB disruption, cell death and astroglial scarring following trauma. Implanted iNSCs could up-regulate brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) levels to support the survival of existing neurons after CHI. In addition, engrafted iNSCs decreased immune cell recruitment and pro-inflammatory cytokine expression in the brain post-injury. Moreover, we found significant nuclear factor-kappaB (NF-κB) inhibition in the presence of iNSC grafts. In short, iNSCs exert neurotrophic and immunomodulatory effects that mitigate CHI-induced neurological impairment.