Dataset Information

Myelinogenic Plasticity of Oligodendrocyte Precursor Cells following Spinal Cord Contusion Injury.

ABSTRACT: Spontaneous remyelination occurs after spinal cord injury (SCI), but the extent of myelin repair and identity of the cells responsible remain incompletely understood and contentious. We assessed the cellular origin of new myelin by fate mapping platelet-derived growth factor receptor ? (PDGFR?), Olig2+, and P0+ cells following contusion SCI in mice. Oligodendrocyte precursor cells (OPCs; PDGFR?+) produced oligodendrocytes responsible for de novo ensheathment of ?30% of myelinated spinal axons at injury epicenter 3 months after SCI, demonstrating that these resident cells are a major contributor to oligodendrocyte regeneration. OPCs also produced the majority of myelinating Schwann cells in the injured spinal cord; invasion of peripheral myelinating (P0+) Schwann cells made only a limited contribution. These findings reveal that PDGFR?+ cells perform diverse roles in CNS repair, as multipotential progenitors that generate both classes of myelinating cells. This endogenous repair might be exploited as a therapeutic target for CNS trauma and disease.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to profound functional deficits, though substantial numbers of axons often survive. One possible explanation for these deficits is loss of myelin, creating conduction block at the site of injury. SCI leads to oligodendrocyte death and demyelination, and clinical trials have tested glial transplants to promote myelin repair. However, the degree and duration of myelin loss, and the extent and mechanisms of endogenous repair, have been contentious issues. Here, we use genetic fate mapping to demonstrate that spontaneous myelin repair by endogenous oligodendrocyte precursors is much more robust than previously recognized. These findings are relevant to many types of CNS pathology, raising the possibility that CNS precursors could be manipulated to repair myelin in lieu of glial transplantation.

SUBMITTER: Assinck P

PROVIDER: S-EPMC6596672 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Myelinogenic Plasticity of Oligodendrocyte Precursor Cells following Spinal Cord Contusion Injury.

Assinck Peggy P Duncan Greg J GJ Plemel Jason R JR Lee Michael J MJ Stratton Jo A JA Manesh Sohrab B SB Liu Jie J Ramer Leanne M LM Kang Shin H SH Bergles Dwight E DE Biernaskie Jeff J Tetzlaff Wolfram W

The Journal of neuroscience : the official journal of the Society for Neuroscience 20170731 36

Spontaneous remyelination occurs after spinal cord injury (SCI), but the extent of myelin repair and identity of the cells responsible remain incompletely understood and contentious. We assessed the cellular origin of new myelin by fate mapping platelet-derived growth factor receptor α (PDGFRα), Olig2+, and P0+ cells following contusion SCI in mice. Oligodendrocyte precursor cells (OPCs; PDGFRα+) produced oligodendrocytes responsible for <i>de novo</i> ensheathment of ∼30% of myelinated spinal a ...[more]

PMID: 28760862

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Project description:Spinal cord injury (SCI) is a severe complication of spinal trauma with high disability and mortality rates. Effective therapeutic methods to alleviate neurobehavioural deficits in patients with SCI are still lacking. In this study, we established a spinal cord contusion (SCC) model in adult Sprague Dawley rats. Induced pluripotent stem cell-derived A2B5+ oligodendrocyte precursor cells (iP-A2B5+OPCs) were obtained from mouse embryonic fibroblasts and injected into the lesion sites of SCC rats. Serological testing and magnetic resonance imaging were employed to determine the effect of iP-A2B5+OPCs cell therapy. The Basso-Beattie-Bresnahan score and inclined plane test were performed on days 1, 3, 7, and 14 after cell transplantation, respectively. Differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) were detected by microarray analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to analyse the biological functions of these lncRNAs and mRNAs. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify variations in the expression of crucial target genes. The results demonstrated that induced pluripotent stem cells exhibited embryonic stem cell-like morphology and could differentiate into diverse neural cells dominated by oligodendrocytes. The neurobehavioural performance of rats treated with iP-A2B5+OPCs transplantation was better than that of rats with SCC without cell transplantation. Notably, we found that 22 lncRNAs and 42 mRNAs were concurrently altered after cell transplantation, and the key lncRNA (NR_037671) and target gene (Cntnap5a) were identified in the iP-A2B5+OPCs group. Moreover, RT-qPCR revealed that iP-A2B5+OPCs transplantation reversed the downregulation of NR_037671 induced by SCC. Our findings indicated that iP-A2B5+OPCs transplantation effectively improves neurological function recovery after SCC, and the mechanism might be related to alterations in the expression of lncRNAs and mRNAs, such as NR_037671 and Cntnap5a.

Project description:Oligodendrocyte precursor cells (OPCs) act as a reservoir of new oligodendrocytes (OLs) in homeostatic and pathological conditions. OPCs are activated in response to injury to generate myelinating OLs, but the underlying mechanisms remain poorly understood. Here, we show that chromodomain helicase DNA binding protein 7 (Chd7) regulates OPC activation after spinal cord injury (SCI). Chd7 is expressed in OPCs in the adult spinal cord and its expression is upregulated with a concomitant increase in Sox2 expression after SCI. OPC-specific ablation of Chd7 in injured mice leads to reduced OPC proliferation, the loss of OPC identity, and impaired OPC differentiation. Ablation of Chd7 or Sox2 in cultured OPCs shows similar phenotypes to those observed in Chd7 knock-out mice. Chd7 and Sox2 form a complex in OPCs and bind to the promoters or enhancers of the regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) genes, thereby inducing their expression. The expression of Rgcc and PKCθ is reduced in the OPCs of the injured Chd7 knock-out mice. In cultured OPCs, overexpression and knock-down of Rgcc or PKCθ promote and suppress OPC proliferation, respectively. Furthermore, overexpression of both Rgcc and PKCθ rescues the Chd7 deletion phenotypes. Chd7 is thus a key regulator of OPC activation, in which it cooperates with Sox2 and acts via direct induction of Rgcc and PKCθ expression.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to oligodendrocyte (OL) loss and demyelination, along with neuronal death, resulting in impairment of motor or sensory functions. Oligodendrocyte precursor cells (OPCs) activated in response to injury are potential sources of OL replacement and are thought to contribute to remyelination and functional recovery after SCI. However, the molecular mechanisms underlying OPC activation, especially its epigenetic regulation, remain largely unclear. We demonstrate here that the chromatin remodeler chromodomain helicase DNA binding protein 7 (Chd7) regulates the proliferation and identity of OPCs after SCI. We have further identified regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) as novel targets of Chd7 for OPC activation.

Project description:Severe traumatic spinal cord injury (SCI) leads to long-lasting oligodendrocyte death and extensive demyelination in the lesion area. Oligodendrocyte progenitor cells (OPCs) are the reservoir of new mature oligodendrocytes during damaged myelin regeneration, which also have latent potential for neurogenic regeneration and oligospheres formation. Whether oligospheres derived OPCs can differentiate into neurons and the neurogenesis potential of OPCs after SCI remains unclear. In this study, primary OPCs cultures were used to generate oligospheres and detect the differentiation and neurogenesis potential of oligospheres. In vivo, SCI models of juvenile and adult mice were constructed. Combining the single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), bioinformatics analysis, immunofluorescence staining, and molecular experiment, we investigated the neurogenesis potential and mechanisms of OPCs in vitro and vivo. We found that OPCs differentiation and oligodendrocyte morphology were significantly different between brain and spinal cord. Intriguingly, we identify a previously undescribed findings that OPCs were involved in oligospheres formation which could further differentiate into neuron-like cells. We also firstly detected the intermediate states of oligodendrocytes and neurons during oligospheres differentiation. Furthermore, we found that OPCs were significantly activated after SCI. Combining scRNA-seq and bulk RNA-seq data from injured spinal cord, we confirmed the neurogenesis potential of OPCs and the activation of endoplasmic reticulum stress after SCI. Inhibition of endoplasmic reticulum stress could effectively attenuate OPCs death. Additionally, we also found that endoplasmic reticulum may regulate the stemness and differentiation of oligospheres. These findings revealed the neurogenesis potential of OPCs from oligospheres and injured spinal cord, which may provide a new source and a potential target for spinal cord repair.

Dataset Information

Myelinogenic Plasticity of Oligodendrocyte Precursor Cells following Spinal Cord Contusion Injury.

Publications

Myelinogenic Plasticity of Oligodendrocyte Precursor Cells following Spinal Cord Contusion Injury.

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