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Brain injuries, such as cerebral hypoxia-ischemia (H-I), induce a regenerative response from the neural stem/progenitors (NSPs) of the subventricular zone (SVZ); however, the mechanisms that regulate this expansion have not yet been fully elucidated. The Notch- Delta-Serrate-Lag2 (DSL) signaling pathway is considered essential for the maintenance of neural stem cells, but it is not known if it is necessary for the expansion of the NSPs subsequent to perinatal H-I injury. Therefore, the aim of this study was to investigate whether this pathway contributes to NSP expansion in the SVZ after H-I and, if so, to establish whether this pathway is directly induced by H-I or regulated by paracrine factors. Here we report that Notch1 receptor induction and one of its ligands, Delta-like 1, precedes NSP expansion after perinatal H-I in P6 rat pups and that this increase occurs specifically in the most medial cell layers of the SVZ where the stem cells reside. Pharmacologically inhibiting Notch signaling in vivo diminished NSP expansion. With an in vitro model of H-I, Notch1 was not induced directly by hypoxia, but was stimulated by soluble factors, specifically leukemia inhibitory factor, produced by astrocytes within the SVZ. These data confirm the importance both of the Notch-DSL signaling pathway in the expansion of NSPs after H-I and in the role of the support cells in their niche. They further support the body of evidence that indicates that leukemia inhibitory factor is a key injury-induced cytokine that is stimulating the regenerative response of the NSPs. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors have no conflicts of interest to report., (© 2016 Wiley Periodicals, Inc.)

REST is a master repressor of neuronal genes; however, whether it has any role during nervous system development remains largely unknown. Here, we analyzed systematically the role of REST in embryonic stem cells and multipotent neural stem/progenitor (NS/P) cells, including neurogenic and gliogenic NS/P cells derived from embryonic stem (ES) cells or developing mouse embryos. We showed that REST-null ES cells remained pluripotent and generated teratomas consisting of the three germ layers. By contrast, multipotent NS/P cells lacking REST displayed significantly reduced self-renewal capacity owing to reduced cell cycle kinetics and precocious neuronal differentiation. Importantly, although early-born neurogenic NS/P cells that lack REST were capable of differentiating to neurons and glia, the neuronal and oligodendrocytic pools were significantly enlarged and the astrocytic pool was shrunken. However, gliogenic NS/P cells lacking REST were able to generate a normal astrocytic pool size, suggesting that the shrinkage of the astrocytic pool generated from neurogenic NS/P cells lacking REST probably occurs by default. Microarray profiling of early-born NS/P cells lacking REST showed upregulation of neuronal as well as oligodendrocytic genes, specifically those involved in myelination. Furthermore, chromatin immunoprecipitation analyses showed that some of the upregulated oligodendrocytic genes contain an RE1 motif and are direct REST targets. Together, our data support a central role for REST during neural development in promoting NS/P cell self-renewal while restricting the generation and maturation of neurons and oligodendrocytes.

Objective: Inflammation promotes epidermal wound healing but is considered detrimental to recovery from central nervous system injury. Sick infants have increased levels of cytokines in their cerebrospinal fluid that correlate with poor neurological outcome. In this study, we investigated the role of neuroinflammation and more specifically interleukin 6 (IL-6) in the amplification of subventricular zone (SVZ) and subgranular zone (SGZ) neural precursors after neonatal brain injury., Methods: Neonatal hypoxia/ischemia (H/I) was induced in P6 rat pups, and IL-6 was quantified with or without indomethacin administration. Neural precursor responses were evaluated by neurosphere assays as well as by stereological analyses. Studies were performed to determine how IL-6 and leukemia-inhibiting factor (LIF) affect SVZ cell expansion, proliferation, and self-renewal., Results: Consistent with earlier studies, medially situated SVZ cells expanded after H/I. Contrary to our expectations, indomethacin significantly decreased both the initial reactive increase in these precursors and their ability to self-renew. By contrast, indomethacin increased proliferation in the SGZ and lateral SVZ. Indomethacin diminished the accumulation of microglia/macrophages and IL-6 production after H/I. In vitro IL-6 enhanced neurosphere growth, self-renewal, and tripotentiality and was more effective than LIF in promoting self-renewal. Enhanced precursor self-renewal also was obtained using prostaglandin E2, which is downstream of cyclooxygenase 2 and a target of indomethacin., Interpretation: These data implicate neuroinflammation and in particular IL-6 as a positive effector of primitive neural precursor expansion after neonatal brain injury. These findings have important clinical implications, as indomethacin and other anti-inflammatory agents are administered to premature infants for a variety of reasons., (Copyright © 2011 American Neurological Association.)