The adult mammal lacks the ability to regenerate neurons lost to retinal damage or disease in a meaningful capacity. However, previous studies from this laboratory have demonstrated that PNU-282987, an α7 nicotinic acetylcholine receptor agonist, elicits a robust neurogenic response in the adult murine retina. With eye drop application of PNU-282987, Müller glia cells re-enter the cell cycle and produce progenitor-like cells that can differentiate into various types of retinal neurons. In this study, we analyzed the regenerative capability of PNU-282987 in two retinal disease models and identified the source of newly regenerated neurons. Wild-type mice and mice with a transgenic Müller-glia lineage tracer were manipulated to mimic loss of retinal cells associated with glaucoma or photoreceptor degeneration. Following treatment with PNU-282987, the regenerative response of retinal neurons was quantified and characterized. After onset of photoreceptor degeneration, PNU-282987 was able to successfully regenerate both rod and cone photoreceptors. Quantification of this response demonstrated significant regeneration, restoring photoreceptors to near wild-type density. In mice that had glaucoma-like conditions induced, PNU-282987 treatment led to a significant increase in retinal ganglion cells. Retrograde labeling of optic nerve axon fibers demonstrated that newly regenerated axons projected into the optic nerve. Lineage tracing analysis demonstrated that these new neurons were derived from Müller glia. These results demonstrate that PNU-282987 can induce retinal regeneration in adult mice following onset of retinal damage. The ability of PNU-282987 to regenerate retinal neurons in a robust manner offers a new direction for developing novel and potentially transformative treatments to combat neurodegenerative disease.

成年哺乳动物缺乏以有意义的能力再生因视网膜损伤或疾病而丢失的神经元的能力。然而，该实验室之前的研究表明，PNU-282987（一种 α7 烟碱乙酰胆碱受体激动剂）可在成年小鼠视网膜中引发强烈的神经源性反应。通过使用 PNU-282987 滴眼液，Müller 胶质细胞重新进入细胞周期并产生可分化为各种类型视网膜神经元的类祖细胞。在本研究中，我们分析了 PNU-282987 在两种视网膜疾病模型中的再生能力，并确定了新再生神经元的来源。野生型小鼠和带有转基因米勒神经胶质细胞谱系示踪剂的小鼠被操纵以模拟与青光眼或感光器变性相关的视网膜细胞损失。使用 PNU-282987 治疗后，对视网膜神经元的再生反应进行了量化和表征。光感受器退化发生后，PNU-282987 能够成功再生视杆细胞和视锥细胞光感受器。这种反应的量化表明了显着的再生，将光感受器恢复到接近野生型的密度。在诱发青光眼样病症的小鼠中，PNU-282987 治疗导致视网膜神经节细胞显着增加。视神经轴突纤维的逆行标记表明新再生的轴突投射到视神经中。谱系追踪分析表明，这些新神经元源自穆勒神经胶质细胞。这些结果表明，PNU-282987 可以在成年小鼠视网膜损伤后诱导视网膜再生。PNU-282987 能够以稳健的方式再生视网膜神经元，为开发新型且具有潜在变革性的治疗方法来对抗神经退行性疾病提供了新的方向。