Adult astrocyte generation across health and disease: A systematic review

Astrocytes are increasingly recognized as dynamic regulators of synaptic, metabolic, vascular, and immune functions in the brain, far beyond their long-assumed supportive role. While adult neurogenesis has been extensively studied, adult astrogliogenesis, the generation of new astrocytes from neural stem cells, the proliferation of mature astrocytes, or the differentiation of oligodendrocyte progenitor cells, remains comparatively underexplored. Emerging evidence indicates that adult astrogliogenesis plays a vital role in maintaining brain homeostasis, responding to injury, and modulating disease progression, with potential therapeutic relevance in neurological and psychiatric disorders. This systematic review followed PRISMA 2020 guidelines and screened 4512 records published between June 2020 and June 2025 across multiple databases, with 17 studies meeting all eligibility criteria. Findings reveal that adult astrogliogenesis occurs under both physiological and pathological conditions, exhibiting notable heterogeneity in origin, regulation, and function. In healthy brains, astrocyte generation is relatively limited, confined mainly to canonical neurogenic niches, the subventricular zone and the hippocampal dentate gyrus, and occurs primarily through local proliferation of mature astrocytes rather than neural stem cell differentiation. Under pathological conditions, astrogliogenesis is consistently upregulated, though outcomes vary across diseases and brain regions. Neurodegenerative disorders, such as Parkinson's and Huntington's diseases, display distinct proliferation patterns between the subventricular zone and the dentate gyrus. In inflammatory conditions, neural stem cell fate shifts toward astrocyte production, often at the expense of neurogenesis. Cerebrovascular injury triggers robust astrocytic proliferation, leading to the formation of protective borders and glial scars. Metabolic disturbances impair proliferation and cognitive function, linking iron homeostasis to astrocyte plasticity. Across all contexts, a key limitation lies in the absence of standardized markers to unequivocally identify newly generated astrocytes and determine their cellular origin. Most studies rely on co-labeling of proliferative and astrocytic markers, which indicate cell division but not lineage derivation. Accurate origin tracing requires genetic fate-mapping approaches, which remain rarely employed in current literature. Overall, adult astrogliogenesis emerges as a dynamic, context-dependent process that can either promote repair or exacerbate pathology. Under homeostatic conditions, stimuli such as deep brain stimulation or exercise may enhance or restore astrogliogenesis. In pathological contexts, proliferation is frequently amplified and accompanied by phenotypic shifts toward reactive states. Understanding these mechanisms could inform therapeutic strategies aimed at modulating astrocyte production to enhance beneficial repair while minimizing detrimental gliosis. Achieving this will require standardized methodologies, precise lineage tracing, and comprehensive mapping of astrocyte subpopulation functions across brain regions.