Localized EMT reprograms glial progenitors to promote spinal cord repair [single-cell RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE164944 | GEO | 2021/01/31
REPOSITORIES: GEO
Similar Datasets
Project description:mCherry/EGFP double positive cells were isolated from the spinal cords of Tg(ctgfa:mCherry; gfap:EGFP) zebrafish at 5 days post injury. Bulk spinal cord tissue at 5, 10, and 21 days post-injury were also sequenced.
2021-01-31 | GSE164943 | GEO
Project description:Anti-regenerative scarring obstructs spinal cord repair in mammals and presents a major hurdle for regenerative medicine. In contrast, adult zebrafish possess specialized glial cells that spontaneously repair spinal cord injuries by forming a pro-regenerative bridge across the severed tissue. To identify the mechanisms that regulate differential regenerative capacity between mammals and zebrafish, we first defined the molecular identity of zebrafish bridging glia and then performed cross-species comparisons with mammalian glia. Our transcriptomics show that pro-regenerative zebrafish glia activate an epithelial-to-mesenchymal transition (EMT) gene program and that EMT gene expression is a major factor distinguishing mammalian and zebrafish glia. Functionally, we found that localized niches of glial progenitors undergo EMT after spinal cord injury in zebrafish and, using large-scale CRISPR-Cas9 mutagenesis, we identified the gene regulatory network that activates EMT and drives functional regeneration. Thus, non-regenerative mammalian glia lack an essential EMT-driving gene regulatory network that reprograms pro-regenerative zebrafish glia after injury.
| S-EPMC8044706 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-01-31 | GSE164945 | GEO
Project description:Localized EMT reprograms glial progenitors to promote spinal cord repair
| PRJNA692492 | ENA
Project description:Localized EMT reprograms glial progenitors to promote spinal cord repair [bulk RNA-seq]
| PRJNA692493 | ENA
Project description:Localized EMT reprograms glial progenitors to promote spinal cord repair [single-cell RNA-seq]
| PRJNA692494 | ENA
Project description:Glial scarring following severe tissue damage and inflammation after spinal cord injury (SCI) is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCI. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCI.
| S-EPMC5561940 | biostudies-other
Project description:In mammals, spinal cord injury results in permanent sensory-motor loss due in part to a failure in reinitiating local neurogenesis. However, zebrafish show robust neuronal regeneration and functional recovery even after complete spinal cord transection. Postembryonic neurogenesis is dependent upon resident multipotent progenitors, which have been identified in multiple vertebrates. One candidate cell population for injury repair expresses Dbx1, which has been shown to label multipotent progenitors in mammals. In this study, we use specific markers to show that cells expressing a dbx1a:GFP reporter in the zebrafish spinal cord are radial glial progenitors that continue to generate neurons after embryogenesis. We also use a novel larval spinal cord transection assay to show that dbx1a:GFP(+) cells exhibit a proliferative and neurogenic response to injury, and contribute newly-born neurons to the regenerative blastema. Together, our data indicate that dbx1a:GFP(+) radial glia may be stem cells for the regeneration of interneurons following spinal cord injury in zebrafish.
| S-EPMC4038170 | biostudies-literature
Project description:BackgroundTransplantation of embryonic stem or neural progenitor cells is an attractive strategy for repair of the injured central nervous system. Transplantation of these cells alone to acute spinal cord injuries has not, however, resulted in robust axon regeneration beyond the sites of injury. This may be due to progenitors differentiating to cell types that support axon growth poorly and/or their inability to modify the inhibitory environment of adult central nervous system (CNS) injuries. We reasoned therefore that pre-differentiation of embryonic neural precursors to astrocytes, which are thought to support axon growth in the injured immature CNS, would be more beneficial for CNS repair.ResultsTransplantation of astrocytes derived from embryonic glial-restricted precursors (GRPs) promoted robust axon growth and restoration of locomotor function after acute transection injuries of the adult rat spinal cord. Transplantation of GRP-derived astrocytes (GDAs) into dorsal column injuries promoted growth of over 60% of ascending dorsal column axons into the centers of the lesions, with 66% of these axons extending beyond the injury sites. Grid-walk analysis of GDA-transplanted rats with rubrospinal tract injuries revealed significant improvements in locomotor function. GDA transplantation also induced a striking realignment of injured tissue, suppressed initial scarring and rescued axotomized CNS neurons with cut axons from atrophy. In sharp contrast, undifferentiated GRPs failed to suppress scar formation or support axon growth and locomotor recovery.ConclusionPre-differentiation of glial precursors into GDAs before transplantation into spinal cord injuries leads to significantly improved outcomes over precursor cell transplantation, providing both a novel strategy and a highly effective new cell type for repairing CNS injuries.
| S-EPMC1561531 | biostudies-literature
Project description:Glial cell types were classified less than 100 years ago by del Rio-Hortega. For instance, he correctly surmised that microglia in pathologic central nervous system (CNS) were "voracious monsters" that helped clean the tissue. Although these historical predictions were remarkably accurate, innovative technologies have revealed novel molecular, cellular, and dynamic physiologic aspects of CNS glia. In this review, we integrate recent findings regarding the roles of glia and glial interactions in healthy and injured spinal cord. The three major glial cell types are considered in healthy CNS and after spinal cord injury (SCI). Astrocytes, which in the healthy CNS regulate neurotransmitter and neurovascular dynamics, respond to SCI by becoming reactive and forming a glial scar that limits pathology and plasticity. Microglia, which in the healthy CNS scan for infection/damage, respond to SCI by promoting axon growth and remyelination-but also with hyperactivation and cytotoxic effects. Oligodendrocytes and their precursors, which in healthy tissue speed axon conduction and support axonal function, respond to SCI by differentiating and producing myelin, but are susceptible to death. Thus, post-SCI responses of each glial cell can simultaneously stimulate and stifle repair. Interestingly, potential therapies could also target interactions between these cells. Astrocyte-microglia cross-talk creates a feed-forward loop, so shifting the response of either cell could amplify repair. Astrocytes, microglia, and oligodendrocytes/precursors also influence post-SCI cell survival, differentiation, and remyelination, as well as axon sparing. Therefore, optimizing post-SCI responses of glial cells-and interactions between these CNS cells-could benefit neuroprotection, axon plasticity, and functional recovery.
| S-EPMC6095774 | biostudies-literature