Pavlou Marina, Probst Marlene, Kaplan Lew, Filippova Elizaveta, Prieve Aric R, Rieke Fred, Reh Thomas A
Department of Neurobiology and Biophysics, University of Washington, Seattle, WA, USA.
Department of Agricultural and Biological Engineering, Purdue University, Lafayette, IN, USA.
EMBO Mol Med. 2025 Apr;17(4):722-746. doi: 10.1038/s44321-025-00209-3. Epub 2025 Mar 6.
The lack of regeneration in the human central nervous system (CNS) has major health implications. To address this, we previously used transgenic mouse models to show that neurogenesis can be stimulated in the adult mammalian retina by driving regeneration programs that other species activate following injury. Expression of specific proneural factors in adult Müller glia causes them to re-enter the cell cycle and give rise to new neurons following retinal injury. To bring this strategy closer to clinical application, we now show that neurogenesis can also be stimulated when delivering these transcription factors to Müller glia using adeno-associated viral (AAV) vectors. AAV-mediated neurogenesis phenocopies the neurogenesis we observed from transgenic animals, with different proneural factor combinations giving rise to distinct neuronal subtypes in vivo. Vector-borne neurons are morphologically, transcriptomically and physiologically similar to bipolar and amacrine/ganglion-like neurons. These results represent a key step forward in developing a cellular reprogramming approach for regenerative medicine in the CNS.
人类中枢神经系统（CNS）缺乏再生能力，这对健康有着重大影响。为了解决这一问题，我们之前利用转基因小鼠模型表明，通过驱动其他物种在受伤后激活的再生程序，可以在成年哺乳动物视网膜中刺激神经发生。在成年穆勒胶质细胞中表达特定的神经发生因子，会使其重新进入细胞周期，并在视网膜损伤后产生新的神经元。为了使这一策略更接近临床应用，我们现在表明，当使用腺相关病毒（AAV）载体将这些转录因子递送至穆勒胶质细胞时，也可以刺激神经发生。AAV介导的神经发生模拟了我们在转基因动物中观察到的神经发生，不同的神经发生因子组合在体内产生不同的神经元亚型。载体携带的神经元在形态、转录组和生理上与双极神经元以及无长突/神经节样神经元相似。这些结果代表了在开发用于中枢神经系统再生医学的细胞重编程方法方面向前迈出的关键一步。
