Hangyuan Jiang , Hengxing Qi , Anying Tang , Shaohua Hu , Jianbo Lai
{"title":"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","authors":"Hangyuan Jiang , Hengxing Qi , Anying Tang , Shaohua Hu , Jianbo Lai","doi":"10.1016/j.arr.2025.102808","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"110 ","pages":"Article 102808"},"PeriodicalIF":12.4000,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Start the engine of neuroregeneration: A mechanistic and strategic overview of direct astrocyte-to-neuron reprogramming\",\"authors\":\"Hangyuan Jiang , Hengxing Qi , Anying Tang , Shaohua Hu , Jianbo Lai\",\"doi\":\"10.1016/j.arr.2025.102808\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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.</div></div>\",\"PeriodicalId\":55545,\"journal\":{\"name\":\"Ageing Research Reviews\",\"volume\":\"110 \",\"pages\":\"Article 102808\"},\"PeriodicalIF\":12.4000,\"publicationDate\":\"2025-06-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ageing Research Reviews\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1568163725001540\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ageing Research Reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1568163725001540","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Start the engine of neuroregeneration: A mechanistic and strategic overview of direct astrocyte-to-neuron reprogramming
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.
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.