Caveolin-1 derived from endothelial cells negatively modulates neuronal differentiation of neural progenitor cells in post-ischemic brain injury

Abstract

Neural progenitor or stem cells (NPCs) can potentially generate new functional neurons for brain repair in post ischemic brains, but its signal mechanisms are largely unknown. Our recent studies indicate that caveolin-1, a 22kDa protein in plasma membrane invaginations, plays critical roles in cell fate decision of NPCs. Caveolin-1 can inhibit neuronal differentiation via down-regulations of VEGF, p44/42MAPK, Akt and Stat3 signaling pathways (PLoS One 2011, 6: e22901), inhibit oligodendroglial differentiation of NPCs through modulating -catenin expression (Neurochem Int 59:114-121, 2011), and promote astroglial differentiation of NPCs through modulating Notch1/NICD and Hes1 expressions( Biochem Biophys Res Commun. 2011;407:517-24). In the present study, we aim to further elucidate whether caveolin-1 could regulate neurogenesis in post-ischemic brains. We first investigated the relationship between caveolin-1 expression and neural differentiations of NPCs in the middle cerebral ischemic rat and mouse brain models. The results revealed that ischemia temporarily down-regulated caveolin-1 expression and promoted neurogenesis in post-ischemic rat brains. However, the expression of caveolin-1 was rebounded and companied with the decrease of neuronal generation in the brains after two weeks of cerebral ischemia. Caveolin-1 was mainly distributed in brain microvascular endothelial cells. Caveolin-1 knockout mice had more abundant newly formed neurons and VEGF positive cells than wild type mice. The new formed neurons were mainly in the granular cell layer of hippocampal dentate gyrus. Thus, we further explored the roles of caveolin-1, derived from brain microvascular endothelial cells (BMVECs), on the neuronal differentiation of NPCs in a co-cultured system in vitro. Co-culture with BMVECs significantly inhibited neuronal differentiation of NPCs. Caveolin-1 RNA silencing treatment abolished the inhibitory effects of BMVECs on the neuronal differentiation of NPCs. Furthermore, caveolin-1 secreted from BMVECs revealed to down-regulate the expressions of VEGF and NeuroD1 and inhibit p44/42MAPK phosphorylation in the co-cultured cell systems. These results indicate that caveolin-1 from BMVECs of the adult ischemic brains could negatively modulate neurogenesis of NPCs by targeting VEGF signaling, NeuroD1 and p44/42MAPK phosphorylation. Down-regulation of caveolin-1 in the vascular niche contributes to enhanced neuronal differentiation in post-ischemic brains.