Lineage specification into GABAergic, glutamatergic, dopaminergic, and astrocytic phenotypes using MUSE stem cells: a novel approach for modeling neurodegenerative and psychiatric disorders

Abstract The study of neurodegenerative and psychiatric disorders is often hampered by the limited accessibility of relevant neural tissues and the limitations of existing in vitro models. MUSE cells (Multilineage differentiating stress enduring), which are non-tumorigenic and stress-resistant stem cells, offer a robust alternative to traditional models such as induced pluripotent stem cells (iPSCs), which suffer from genetic variability and residual epigenetic memory. Possessing key pluripotency markers such as NANOG, OCT3/4, and SOX2, and capable of differentiating into all three germ layers, MUSE cells are ideally suited for both research and therapeutic applications. In this study, we have developed protocols for differentiating MUSE cells into neural progenitors, providing a critical foundation for modeling early neural development and dysfunction. These neural progenitors were then directed to specify into GABAergic, glutamatergic, dopaminergic neurons, and astrocytes, enabling detailed studies of specific lineage dysfunctions associated with neurodegenerative and psychiatric conditions such as schizophrenia, bipolar disorder, and Alzheimer’s disease. This approach not only enhances the physiological relevance of our models but also allows us to investigate the cellular mechanisms underlying these complex diseases more effectively. By improving our understanding of neural lineage specification and early developmental alterations, MUSE cells facilitate the development of targeted therapies and reduce reliance on animal models, thus advancing the path from research to clinical applications.