PDF(Pubmed)
Abstract：
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.
摘要：
严重的创伤性脊髓损伤（SCI）导致持久的少突胶质细胞死亡和病变区域的广泛脱髓鞘。少突胶质祖细胞(OPCs)是受损髓鞘再生过程中新的成熟少突胶质细胞的储库,也具有潜在的神经源性再生和寡球形成的潜力。脊髓损伤后OPCs是否能分化为神经元和神经发生潜能尚不清楚。在这项研究中,原代OPCs培养物用于产生寡球并检测寡球的分化和神经发生潜力。在体内,构建了幼年和成年小鼠的SCI模型。结合单细胞RNA测序（scRNA-seq），批量RNA测序（RNA-seq），生物信息学分析，免疫荧光染色，和分子实验，我们研究了OPCs在体外和体内的神经发生潜力和机制。我们发现脑和脊髓之间的OPCs分化和少突胶质细胞形态显着不同。有趣的是，我们确定了以前未描述的发现，即OPC参与了可以进一步分化为神经元样细胞的寡球体形成。我们还首次检测了少突胶质细胞和神经元在少突胶质细胞分化过程中的中间状态。此外，我们发现OPCs在SCI后被显著激活。结合scRNA-seq和来自受损脊髓的大量RNA-seq数据，我们证实了OPCs的神经发生潜力和SCI后内质网应激的激活。抑制内质网应激可有效减轻OPCs死亡。此外,我们还发现内质网可能调节寡球体的干性和分化。这些发现揭示了OPCs的神经发生潜力来自少球和受损的脊髓，这可能为脊髓修复提供新的来源和潜在的目标。
