Old enough to be a model? On the role of maturity in stem cell-based models for neuropsychiatric disorders

TL;DR

This paper reviews how stem cell models can better reflect the biology of mental disorders by considering the maturity of cells used in experiments.

Contribution

The paper emphasizes the importance of developmental timing in stem cell models for understanding late-onset mental disorders.

Findings

Current iPSC-derived models resemble fetal brain tissue, limiting their relevance for late-onset disorders.

Developmental timing affects the interpretation of iPSC-based findings in neuropsychiatric research.

Emerging methods aim to accelerate or extend neuronal aging in vitro for better disease modeling.

Abstract

Mental disorders profoundly influence cognition, emotion, and self-perception, and collectively represent a major cause of global disability. Their onset spans distinct developmental periods, from early childhood in neurodevelopmental conditions such as autism spectrum disorder, through adolescence in eating and obsessive-compulsive disorders, to early adulthood in bipolar disorder and schizophrenia. Twin and family studies have established that these disorders are substantially heritable, and large-scale genomic analyses have identified numerous common and rare risk variants. Yet, the biological mechanisms through which genetic and environmental factors converge to shape disease trajectories remain elusive. Patient-derived induced pluripotent stem cells (iPSCs) have emerged as a promising tool for investigating disease-relevant mechanisms in human neurons and neural circuits. However, most iPSC-derived neural cells and organoids resemble embryonic/fetal-stage brain tissue in both molecular and functional characteristics, raising questions about their relevance for disorders that manifest later in life. In this narrative review, we discuss how developmental timing, both in disease onset and in cellular models, shapes the interpretation of iPSC-based findings. We outline how differences in neuronal maturity may constrain or enable mechanistic insight, summarize emerging methods for accelerating or extending neuronal aging in vitro, and consider how leveraging developmental immaturity might illuminate early pathogenic processes underlying mental disorders.

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