Start the engine of neuroregeneration: A mechanistic and strategic overview of direct astrocyte-to-neuron reprogramming

IF 12.4 1区 医学 Q1 CELL BIOLOGY
Hangyuan Jiang , Hengxing Qi , Anying Tang , Shaohua Hu , Jianbo Lai
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Abstract

The decline of adult neurogenesis and neuronal function during aging underlies the onset and progression of neurodegenerative diseases such as Alzheimer’s disease. Conventional therapies, including neurotransmitter modulators and antibodies targeting pathogenic proteins, offer only symptomatic improvement. As the most abundant glial cells in the brain, astrocytes outnumber neurons nearly fivefold. However, their proliferative and transdifferentiation potential renders them ideal candidates for in situ neuronal replacement. Direct astrocyte-to-neuron reprogramming offers a promising regenerative approach to restore damaged neural circuits. Herein, we propose a “car start-up” model to conceptualize this process, emphasizing the need to inhibit non-neuronal fate pathways (release the handbrake), suppress transcriptional repressors (release the footbrake), and activate neuron-specific gene expression (step on the gas). Additionally, overcoming metabolic barriers in the cytoplasm is essential for successful lineage conversion. Viral or non-viral vectors deliver reprogramming factors, while small molecules serve as metabolic and epigenetic fuel to boost efficiency. In summary, we review the current evidence supporting direct astrocyte-to-neuron reprogramming as a viable regenerative strategy in the aging brain. We also highlight the conceptual “car start-up” model as a useful framework to dissect the molecular logic of lineage conversion and emphasize its promising therapeutic potential for combating neurodegenerative diseases.
启动神经再生引擎:直接星形胶质细胞到神经元重编程的机制和策略概述
在衰老过程中,成人神经发生和神经元功能的下降是神经退行性疾病(如阿尔茨海默病)的发生和发展的基础。传统疗法,包括神经递质调节剂和针对致病蛋白的抗体,只能提供症状改善。作为大脑中最丰富的神经胶质细胞,星形胶质细胞的数量几乎是神经元的五倍。然而,它们的增殖和转分化潜力使它们成为原位神经元替代的理想候选者。星形胶质细胞到神经元的直接重编程为修复受损的神经回路提供了一种有前途的再生方法。在此,我们提出了一个“汽车启动”模型来概念化这一过程,强调需要抑制非神经元命运通路(释放手刹),抑制转录抑制因子(释放脚刹),并激活神经元特异性基因表达(踩油门)。此外,克服细胞质中的代谢障碍对于成功的谱系转换至关重要。病毒或非病毒载体传递重编程因子,而小分子则作为代谢和表观遗传燃料来提高效率。总之,我们回顾了目前支持星形胶质细胞到神经元的直接重编程作为衰老大脑中可行的再生策略的证据。我们还强调了概念上的“汽车启动”模型作为一个有用的框架来剖析谱系转换的分子逻辑,并强调其在对抗神经退行性疾病方面的治疗潜力。
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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