Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes (original) (raw)
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Neural progenitor cells regulate microglia functions and activity
Nature Neuroscience, 2012
We observed that mouse neural progenitor cells (NPCs) have a secretory protein profile distinct from other brain cells and modulate microglial activation, proliferation, and phagocytosis in culture and in vivo. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Neural stem or precursor cells may thus not only be shaped by microglia but regulate in turn microglia functions and activity. Neural stem cells (NSCs) in the adult mammalian brain can give rise to rapidly dividing neural progenitor cells (NPCs) to produce neurons, astrocytes and oligodendrocytes and functionally contribute to cognition and repair processes after injury 1. Cultured stem cells derived from adult or neonatal brains typically contain few NSCs and are made up mostly of NPCs instead 2. Transplanted NPCs, even in small numbers, have beneficial effects on recovery from CNS trauma or disease 3, 4 , but the mechanisms of action remain unclear. And while increasing evidence shows how local environmental cues, including microglia and Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Interplay between human microglia and neural stem/progenitor cells in an allogeneic co-culture model
Journal of Cellular and Molecular Medicine, 2013
Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-b was increased suggesting antiinflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.
Microglia: dismantling and rebuilding circuits after acute neurological injury
Metabolic Brain Disease, 2014
The brain is comprised of neurons and its support system including astrocytes, glial cells and microglia, thereby forming neurovascular units. Neurons require support from glial cells to establish and maintain functional circuits, but microglia are often overlooked. Microglia function as the immune cell of the central nervous system, acting to monitor the microenvironment for changes in signaling, pathogens and injury. More recently, other functional roles for microglia within the healthy brain have been identified, including regulating synapse formation, elimination and function. This review aims to highlight and discuss these alternate microglial roles in the healthy and in contrast, diseased brain with a focus on two acute neurological diseases, traumatic brain injury and epilepsy. In these conditions, microglial roles in synaptic stripping and stabilization as part of neuronal:glial interactions may position them as mediators of the transition between injury-induced circuit dismantling and subsequent reorganization. Increased understanding of microglia roles could identify therapeutic targets to mitigate the consequences of neurological disease. Microglia: Amoeboid to ramified and back again Microglial morphology has long been interpreted to follow function, with surface antigens changing dependent on the stimulus for activation and the role required to play in the brain. This simplistic view is now being challenged, with data collected over the previous decades indicating alternate roles for microglia, particularly in the uninjured brain. During development of the brain, microglial precursors undergo three developmental milestones toward becoming fully integrated microglia. Microglia proliferate and migrate to populate different central nervous system (CNS) regions, and then differentiate from an amoeboidlike form into their ramified morphology. Within the non-pathological brain, ramified microglia constantly survey the microenvironment by movement of their fine processes, sampling the surface of cells and interstitial fluid in their immediate vicinity [1, 2] and
EXCLI Journal, 2020
Microglial cells are the primary immune cells in the central nervous system. In the mature brain, microglia perform functions that include eliminating pathogens and clearing dead/dying cells and cellular debris through phagocytosis. In the immature brain, microglia perform functions that include synapse development and the regulation of cell production through extensive contact with and phagocytosis of neural progenitor cells (NPCs). However, the functional role of microglia in the proliferation and differentiation of NPCs under hypoxic-ischemic (HI) injury is not clear. Here, we tested the hypothesis that microglia enhance NPCs proliferation following HI insult. Primary NPCs cultures were divided into four treatment groups: 1) normoxic NPCs (NN); 2) normoxic NPCs cocultured with microglia (NN+M); 3) hypoxic NPCs (HN); and 4) hypoxic NPCs cocultured with microglia (HN+M). Hypoxic-ischemic injury was induced by pretreatment of the cell cultures with 100 µM deferoxamine mesylate (DFO)...
Glia, 2008
The contribution of microglia to the modulation of neurogenesis under pathological conditions is unclear. Both proand anti-neurogenic effects have been reported, likely reflecting the complexity of microglial activation process. We previously demonstrated that prolonged (72 hr) in vitro exposure to lipopolysaccharide (LPS) endows microglia with a potentially neuroprotective phenotype, here referred as to ''chronic''. In the present study we further characterized the chronic phenotype and investigated whether it might differently regulate the properties of embryonic and adult neural precursor cells (NPC) with respect to the ''acute'' phenotype acquired following a single (24 hr) LPS stimulation. We show that the LPS-dependent induction of the proinflammatory cytokines interleukin (IL)-1a, IL-1b, IL-6, and tumor necrosis factor (TNF)-a was strongly reduced after chronic stimulation of microglia, as compared with acute stimulation. Conversely, the synthesis of the anti-inflammatory cytokine IL-10 and the immunomodulatory prostaglandin E 2 (PGE 2 ) was still elevated or further increased, after chronic LPS exposure, as revealed by real time PCR and ELISA techniques. Acutely activated microglia, or their conditioned medium, reduced NPC survival, prevented neuronal differentiation and strongly increased glial differentiation, likely through the release of proinflammatory cytokines, whereas chronically activated microglia were permissive to neuronal differentiation and cell survival, and still supported glial differentiation. Our data suggest that, in a chronically altered environment, persistently activated microglia can display protective functions that favor rather than hinder brain repair processes. V V C
Glia, 2009
Neural stem cells (NSCs) in the adult rat subventricular zone (SVZ) generate new striatal neurons during several months after ischemic stroke. Whether the microglial response associated with ischemic injury extends into SVZ and influences neuroblast production is unknown. Here, we demonstrate increased numbers of activated microglia in ipsilateral SVZ concomitant with neuroblast migration into the striatum at 2, 6, and 16 weeks, with maximum at 6 weeks, following 2 h middle cerebral artery occlusion in rats. In the peri-infarct striatum, numbers of activated microglia peaked already at 2 weeks and declined thereafter. Microglia in SVZ were resident or originated from bone marrow, with maximum proliferation during the first 2 weeks postinsult. In SVZ, microglia exhibited ramified or intermediate morphology, signifying a downregulated inflammatory profile, whereas amoeboid or round phagocytic microglia were frequent in the peri-infarct striatum. Numbers of microglia expressing markers of antigen-presenting cells (MHC-II, CD86) increased in SVZ but very few lymphocytes were detected. Using quantitative PCR, strong short- and long-term increase (at 1 and 6 weeks postinfarct) of insulin-like growth factor-1 (IGF-1) gene expression was detected in SVZ tissue. Elevated numbers of IGF-1-expressing microglia were found in SVZ at 2, 6, and 16 weeks after stroke. At 16 weeks, 5% of microglia but no other cells in SVZ expressed the IGF-1 protein, which mitigates apoptosis and promotes proliferation and differentiation of NSCs. The long-term accumulation of microglia with proneurogenic phenotype in the SVZ implies a supportive role of these cells for the continuous neurogenesis after stroke. © 2008 Wiley-Liss, Inc.
Molecular and Cellular Neuroscience, 2011
Ionizing radiation results in damage to neural stem cells and reduced neurogenesis. The aim of the present study was to determine intrinsic and extrinsic factors that influence neural stem cell survival following irradiation, using qPCR. Gene expression of hippocampal and SVZ neurospheres were analyzed following irradiation, and results demonstrated that irradiated hippocampal and SVZ stem cells displayed similar gene expression profiles for intrinsic genes. Irradiated microglia (extrinsic factor) isolated from the SVZ exhibited increased gene expression of growth factors involved in stem cell maintenance, proliferation, and survival. However, microglial genes in the irradiated hippocampus responded less favorably with respect to stem cell recovery. This might explain the superior recovery of SVZ compared to hippocampal stem cells following in vivo irradiation. In addition, our results show that a combination of growth factors, which were upregulated in SVZ microglia, increased the proliferation and decreased cell death of irradiated neurospheres in vitro.
Microglial repopulation resolves inflammation and promotes brain recovery after injury
Glia, 2017
Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use. Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS, affording an opportunity to renew this cellular compartment. To that end, we have explored the effects of acute microglial elimination, followed by microglial repopulation, in a mouse model of extensive neuronal loss. Neuronal loss leads to a prolonged neuroinflammatory response, characterized by the presence of swollen microglia expressing CD68 and CD45, as wel...
Glia, 2005
Reactive microgliosis is a highly characteristic response to neural injury and disease, which may influence neurodegenerative processes and neural plasticity. We have investigated the origin and characteristics of reactive microglia in the acute phase of their activation in the dentate gyrus following transection of the entorhino-dentate perforant path projection. To investigate the possible link between microglia and hematopoietic precursors, we analyzed the expression of the stem cell marker CD34 by lesion-reactive microglia in conjunction with the proliferation marker bromodeoxyuridine (BrdU) and the use of radiation bone marrow (BM) chimeric mice. We found that CD34 is upregulated on early-activated resident microglia, rather than by infiltrating bone marrow-derived cells. The number of CD34 + microglia peaked at day 3 when 67% of the resident CD11b/Mac-1 + microglia co-expressed CD34, and all CD34 + cells co-expressed Mac-1, and decreased sharply toward day 5, unlike Mac-1, which was maximally expressed at day 5. Approximately 80% of the CD34 + cells in the denervated dentate gyrus had incorporated BrdU into their nuclei at day 3. We also showed that CD34 is upregulated on early-activated microglia in the facial motor nucleus following peripheral axotomy. The results suggest lesionreactive microglia to consist of functionally distinct subpopulations of cells; a major population of activated resident CD34 + Mac-1 + microglia with a high capacity for selfrenewal, and a subpopulation of CD34 À Mac-1 + microglia which has a mixed extrinsic and intrinsic origin and whose proliferative capacity is unknown. '