Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Dev Cell. 2021 Mar 8;56(5):613-626.e7. doi: 10.1016/j.devcel.2021.01.017. Epub 2021 Feb 19.
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.
抗再生性瘢痕阻碍了哺乳动物脊髓的修复，这也是再生医学的主要障碍。相比之下，成年斑马鱼拥有专门的神经胶质细胞，这些细胞能够通过在切断的组织上形成一个有利于再生的桥来自发修复脊髓损伤。为了确定调节哺乳动物和斑马鱼之间不同再生能力的机制，我们首先定义了斑马鱼桥接神经胶质细胞的分子特征，然后与哺乳动物神经胶质细胞进行了跨物种比较。我们的转录组学研究表明，有利于再生的斑马鱼神经胶质细胞会激活上皮-间充质转化（EMT）基因程序，而 EMT 基因表达是区分哺乳动物和斑马鱼神经胶质细胞的主要因素。在功能上，我们发现斑马鱼脊髓损伤后，神经胶质前体细胞的局部龛位会经历 EMT，并且通过大规模的 CRISPR-Cas9 基因敲除，我们鉴定出了激活 EMT 并驱动功能再生的基因调控网络。因此，非再生性的哺乳动物神经胶质细胞缺乏一种必要的 EMT 驱动的基因调控网络，而这种网络可以在损伤后对有利于再生的斑马鱼神经胶质细胞进行重新编程。
