Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Neurological Surgery, Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cell Stem Cell. 2021 May 6;28(5):923-937.e4. doi: 10.1016/j.stem.2021.02.009. Epub 2021 Mar 5.
Adult neurogenesis plays critical roles in maintaining brain homeostasis and responding to neurogenic insults. However, the adult mammalian spinal cord lacks an intrinsic capacity for neurogenesis. Here we show that spinal cord injury (SCI) unveils a latent neurogenic potential of NG2+ glial cells, which can be exploited to produce new neurons and promote functional recovery after SCI. Although endogenous SOX2 is required for SCI-induced transient reprogramming, ectopic SOX2 expression is necessary and sufficient to unleash the full neurogenic potential of NG2 glia. Ectopic SOX2-induced neurogenesis proceeds through an expandable ASCL1+ progenitor stage and generates excitatory and inhibitory propriospinal neurons, which make synaptic connections with ascending and descending spinal pathways. Importantly, SOX2-mediated reprogramming of NG2 glia reduces glial scarring and promotes functional recovery after SCI. These results reveal a latent neurogenic potential of somatic glial cells, which can be leveraged for regenerative medicine.
成人神经发生在维持大脑内稳态和应对神经发生损伤方面起着关键作用。然而，成年哺乳动物的脊髓缺乏内在的神经发生能力。在这里，我们发现脊髓损伤 (SCI) 揭示了 NG2+ 神经胶质细胞的潜在神经发生潜力，这可以被利用来产生新的神经元，并促进 SCI 后的功能恢复。尽管内源性 SOX2 是 SCI 诱导的瞬时重编程所必需的，但异位 SOX2 表达是释放 NG2 胶质细胞完全神经发生潜力所必需且充分的。异位 SOX2 诱导的神经发生通过可扩展的 ASCL1+祖细胞阶段进行，并产生兴奋性和抑制性 propriospinal 神经元，与上升和下降的脊髓通路建立突触连接。重要的是，SOX2 介导的 NG2 胶质细胞重编程减少了神经胶质瘢痕的形成，并促进了 SCI 后的功能恢复。这些结果揭示了体细胞神经胶质细胞的潜在神经发生潜力，可用于再生医学。
