Cavone Leonardo, McCann Tess, Drake Louisa K, Aguzzi Erika A, Oprişoreanu Ana-Maria, Pedersen Elisa, Sandi Soe, Selvarajah Jathurshan, Tsarouchas Themistoklis M, Wehner Daniel, Keatinge Marcus, Mysiak Karolina S, Henderson Beth E P, Dobie Ross, Henderson Neil C, Becker Thomas, Becker Catherina G
Centre for Discovery Brain Sciences, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
Centre for Discovery Brain Sciences, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK; Max Planck Institute for the Science of Light, Staudtstraße 2, Erlangen 91058, Germany; Max-Planck-Zentrum für Physik und Medizin, Staudtstraße 2, Erlangen 91058, Germany.
Dev Cell. 2021 Jun 7;56(11):1617-1630.e6. doi: 10.1016/j.devcel.2021.04.031. Epub 2021 May 24.
Central nervous system injury re-initiates neurogenesis in anamniotes (amphibians and fishes), but not in mammals. Activation of the innate immune system promotes regenerative neurogenesis, but it is fundamentally unknown whether this is indirect through the activation of known developmental signaling pathways or whether immune cells directly signal to progenitor cells using mechanisms that are unique to regeneration. Using single-cell RNA-seq of progenitor cells and macrophages, as well as cell-type-specific manipulations, we provide evidence for a direct signaling axis from specific lesion-activated macrophages to spinal progenitor cells to promote regenerative neurogenesis in zebrafish. Mechanistically, TNFa from pro-regenerative macrophages induces Tnfrsf1a-mediated AP-1 activity in progenitors to increase regeneration-promoting expression of hdac1 and neurogenesis. This establishes the principle that macrophages directly communicate to spinal progenitor cells via non-developmental signals after injury, providing potential targets for future interventions in the regeneration-deficient spinal cord of mammals.
中枢神经系统损伤会在无羊膜动物（两栖动物和鱼类）中重新启动神经发生，但在哺乳动物中不会。先天免疫系统的激活促进再生性神经发生，但根本不清楚这是通过激活已知的发育信号通路间接实现的，还是免疫细胞利用再生特有的机制直接向祖细胞发出信号。通过对祖细胞和巨噬细胞进行单细胞RNA测序以及细胞类型特异性操作，我们提供了证据，证明在斑马鱼中存在一条从特定损伤激活的巨噬细胞到脊髓祖细胞的直接信号轴，以促进再生性神经发生。从机制上讲，促再生巨噬细胞产生的肿瘤坏死因子α（TNFa）诱导祖细胞中Tnfrsf1a介导的AP-1活性，以增加促进再生的组蛋白去乙酰化酶1（hdac1）表达和神经发生。这确立了一个原则，即损伤后巨噬细胞通过非发育信号直接与脊髓祖细胞通信，为未来干预哺乳动物再生缺陷脊髓提供了潜在靶点。
