Multilineage-Differentiating Stress-Enduring (MUSE) Cells as an Innovative In Vitro Cellular Model to Study Mood and Psychotic Disorders

Psychotic and mood disorders, including schizophrenia (SCZ) and bipolar disorder (BD), are complex neurodevelopmental conditions marked by synaptic dysfunctions, aberrant neurogenesis, and gene–environment interactions. Studying these disorders remains challenging due to the inaccessibility of live brain tissue and the limitations of currently available in vitro models. To overcome these barriers, we explored the use of MUSE (Multilineage-differentiating Stress-Enduring) cells as a new in vitro model system to study disease-related neuronal alterations. Muse cells are endogenous pluripotent-like stem cells, non-tumorigenic, identifiable by SSEA-3 positivity, capable of spontaneous differentiation into cell types from all three germ layers and uniquely resistant to cellular stress. These characteristics makes them an attractive and innovative tool for several disease modeling. This research explores the potential of Muse cells as an innovative in vitro model for investigating the cellular and molecular alterations associated with bipolar disorder (BD) and schizophrenia (SCZ) and to reveal neurodevelopmental impairments at both the stem and progenitor stages of differentiation. This multicentric study involves six recruitment centers distributed across the Italian territory, collectively enrolling over 100 male participants. Muse cells were isolated from dermal stromal tissue using minimally invasive 1.5 mm punch biopsies from healthy controls and diagnosed SCZ and BD patients, then induced toward neural and glial differentiation. Cells were selected via magnetic-activated cell sorting (MACS) based on SSEA-3 expression and assessed for stemness (OCT3/4, SOX2, NANOG), cell cycle profile, apoptosis (Annexin-V), and senescence (β-galactosidase). Neural induction protocols developed in-house allowed the stepwise differentiation of Muse cells through neural progenitor stages into GABAergic and glutamatergic neurons, enabling the tracking of functional and morphological changes throughout the entire neurodevelopmental trajectory. Results demonstrated that MUSE cells derived from SCZ and BD patients exhibited significantly lower stemness marker expression, reduced S-phase representation, and higher apoptosis, indicating compromised regenerative potential. Furthermore, analysis of neural progenitor intermediates uncovered disease-specific deficits in early neurogenic commitment. Final stage committed neurons showed altered morphology and reduced expression of MAP2 (neuronal marker), GAD1/2 (GABAergic), and DAT (dopaminergic). These findings support the validity of MUSE cells as a biologically relevant and robust model for investigating molecular and cellular mechanisms underlying psychotic and mood disorders. Despite limitations such as sample size and inter-individual variability, this model offers an accessible and physiologically sound alternative to current stem cell-based platforms. Notably, MUSE cells may serve as a valuable translational tool not only for in vitro studies but also for pharmacological screening and the development of personalized therapeutic strategies. In conclusion, MUSE cells stand out as an innovative and promising in vitro model with the potential to transform neuropsychiatric research and therapy development.