Abstract
Functional signaling between neural stem/progenitor cells (NSPCs) and brain endothelial cells (ECs) is essential to the coordination of organized responses during initial embryonic development and also during tissue repair, which occurs following brain injury. In this study, we investigated the molecular mechanisms underlying this functional signaling, using primary mouse brain ECs and NSPCs from embryonic mouse brain. EC/NSPC co-culture experiments have revealed that neural progenitors secrete factors supporting angiogenesis, which induce noticeable changes in endothelial morphology. We demonstrate that NSPCs influence the expression of mTOR and TGF-β signaling pathway components implicated in the regulation of angiogenesis. Endothelial morphogenesis, an essential component of vascular development, is a complex process involving gene activation and the upregulation of specific cell signaling pathways. Recently identified small molecules, called microRNAs (miRNAs), regulate the expression of genes and proteins in many tissues, including brain and vasculature. We found that NSPCs induced considerable changes in the expression of at least 24 miRNAs and 13 genes in ECs. Three NSPC-regulated EC miRNAs were identified as the potential primary mediators of this NSPC/EC interaction. We found that the specific inhibition, or overexpression, of miRNAs miR-155, miR-100, and miR-let-7i subsequently altered the expression of major components of the mTOR, TGF-β and IGF-1R signaling pathways in ECs. Overexpression of these miRNAs in ECs suppressed, while inhibition activated, the in vitro formation of capillary-like structures, a process representative of EC morphogenesis. In addition, we demonstrate that inhibition of FGF, VEGF, and TGF-β receptor signaling abolished NSPC-promoted changes in the endothelial miRNA profiles. Our findings demonstrate that NSPCs induce changes in the miRNA expression of ECs, which are capable of activating angiogenesis by modulating distinct cell signaling pathways.
Highlights
There is a close association and reciprocal signaling that occurs between endothelial cells (ECs) and neural stem/progenitor cells (NSPCs) in the neurogenic zones of the adult brain
In our previous studies on NSPC-induced EC morphogenesis, we primarily focused on the molecules and signaling pathways effected in NSPCs
The significant changes in EC morphology observed in our present study, were not initiated by either the growth medium or supporting substrate, but rather were influenced by the diffusible factors released by NSPCs in our segregated coculture system
Summary
There is a close association and reciprocal signaling that occurs between ECs and NSPCs in the neurogenic zones of the adult brain. Recognition of this close relationship has led to the descriptive concept of a "neurovascular niche", where endothelial and neural cells interact with each other, both prior to and throughout their maturation. As an essential component of vascular development, endothelial morphogenesis is a complex process involving gene activation and upregulation of specific cell signaling pathways. Recent findings demonstrate that miRNAs control neurogenesis [ 6, 7] and could help regulate the morphogenesis of endothelial cells [ 8, 9]. The role of miRNAs in EC function currently remains unclear, and only a few specific miRNAs targeting endothelial cell function and angiogenesis have been identified. miRNAs including the mir-let-7 family, as well as mir-21, mir-126, mir-221, and mir-222 are highly expressed in endothelial cells [ 9, 10]
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