LAUSR

In hypoxic-ischemic encephalopathy, the Neural Progenitors (NPs) of the developing brain fail to replenish the oligodendrocyte progenitor cells lost during hypoxic-ischemic injury (HII). Here, we aim to examine the influence of HII on the vulnerability of human NPs derived from human embryonic stem cells (hESCs) with regard to cell survival and oxidative stress, followed by assessment of cellular deregulation through measuring glutathione-levels, basal-calcium, glutamate-release and intracellular-calcium [Ca2+]i response under KCl and ATP stimulation. NPs were further evaluated for their fundamental-potential of self-renewal & proliferation, neural and glial progenitor pool and migration. Oxygen-glucose-deprivation(OGD) of 90mins was sub-lethal for NPs yet significantly increased ROS generation, oxidative-stress susceptibility and decreased glutathione-levels, along with a rise in glutamate release, basal [Ca2+]i and KCl and ATP-induced [Ca2+]i. Distinct increase in gene-expression for K+ leak channel(TASK1), purinergic-receptor P2X7 and decrease of voltage-gated Kv-channels Kv1.5, Kv4.2 & Kv4.3 were observed. OGD-insulted NPs showed reduced migration-potential and decline in glial-progenitor population. Our present study thus demonstrates for the first time that brief exposure of OGD does not reduce the neural progenitor population, its proliferation and self-renewal but can induce significant alteration in oxidative-stress susceptibility, glutamate release, [Ca2+]i response to physiological stimulus, migration and glial-progenitor pool. We thus infer that treatment strategies need to target repair of NPs of the developing brain that is affected during intra-partum asphyxia leading to varying neurologic complications such as seizure, mental retardation and/or cerebral palsy.