Endogenous reprogramming of glia into neurogenic progenitors holds great promise for neuron restoration therapies. Using lessons from regenerative species, we have developed strategies to stimulate mammalian Müller glia to regenerate neurons in vivo in the adult retina. We have demonstrated that the transcription factor Ascl1 can stimulate Müller glia neurogenesis. However, Ascl1 is only able to reprogram a subset of Müller glia into neurons. We have reported that neuroinflammation from microglia inhibits neurogenesis from Müller glia. Here we found that the peripheral immune response is a barrier to CNS regeneration. We show that monocytes from the peripheral immune system infiltrate the injured retina and negatively influence neurogenesis from Müller glia. Using CCR2 knock-out mice of both sexes, we found that preventing monocyte infiltration improves the neurogenic and proliferative capacity of Müller glia stimulated by Ascl1. Using scRNA-seq analysis, we identified a signaling axis wherein Osteopontin, a cytokine highly expressed by infiltrating immune cells is sufficient to suppress mammalian neurogenesis. This work implicates the response of the peripheral immune system as a barrier to regenerative strategies of the retina.

神经胶质细胞内源性重编程为神经源性祖细胞为神经元恢复疗法带来了巨大的前景。利用再生物种的经验教训，我们开发了刺激哺乳动物 Müller 神经胶质细胞在成人视网膜体内再生神经元的策略。我们已经证明转录因子 Ascl1 可以刺激 Müller 神经胶质细胞神经发生。然而，Ascl1 只能将 Müller 神经胶质细胞的一个子集重编程为神经元。我们已经报道了来自小胶质细胞的神经炎症抑制了来自 Müller 胶质细胞的神经发生。在这里，我们发现外周免疫反应是 CNS 再生的障碍。我们表明，来自外周免疫系统的单核细胞浸润受伤的视网膜，并对 Müller 胶质细胞的神经发生产生负面影响。使用两性的 CCR2 敲除小鼠，我们发现防止单核细胞浸润可以提高 Ascl1 刺激的 Müller 胶质细胞的神经源性和增殖能力。使用 scRNA-seq 分析，我们确定了一个信号轴，其中骨桥蛋白是一种通过浸润免疫细胞高度表达的细胞因子，足以抑制哺乳动物的神经发生。这项工作涉及外周免疫系统的反应作为视网膜再生策略的屏障。