Impaired Neurosphere Formation as a Functional Readout of Aberrant EGFR Signaling Kinetics in Olfactory Neural Progenitors From Patients With Schizophrenia

ABSTRACT

The Epidermal Growth Factor Receptor (EGFR) is a key regulator of neurodevelopment, controlling the proliferation, differentiation, and self‐renewal of neural stem and progenitor cells. Dysregulated EGFR signaling has been implicated in schizophrenia, a neurodevelopmental disorder associated with abnormal cortical maturation. We investigated EGFR‐dependent signaling in neural stem/progenitor cells derived from olfactory neuroepithelium (hereafter referred to as Olfactory Neural Stem/Progenitor Cells, ONSPCs) collected from individuals with no prior history of psychiatric disorders (hereafter referred to as healthy controls, HC) and patients diagnosed with schizophrenia (schizophrenic, SZ), an ex vivo human model that retains disease‐related molecular signatures. Both HC‐ and SZ‐derived ONSPCs formed neurospheres under proliferative conditions in the presence of the growth factors Epidermal Growth Factor (EGF) and Fibroblast Growth Factor (FGF), confirming their neural progenitor identity. However, under EGF‐exclusive conditions, HC‐derived ONSPCs generated compact, well‐organized neurospheres, whereas SZ‐derived ONSPCs produced sparse, irregular aggregates, indicating impaired responsiveness to EGF. Despite comparable EGFR protein levels between groups, EGF stimulation revealed distinct dynamics of downstream EGFR effectors. In HC‐derived ONSPCs, EGFR activation was initially modest but sustained over time, whereas in SZ‐derived cells it was more rapid and transiently stronger, followed by early signal decay. In particular, Akt and Src, which are implicated in signaling pathways driving proliferation and self‐renewal, displayed activation dynamics paralleling those of EGFR in each group. These findings are consistent with dysregulation of the magnitude and temporal dynamics of EGFR–dependent signaling in SZ‐derived ONSPCs, associated with impaired neurosphere formation under EGF‐exclusive conditions and suggestive of reduced self‐renewal capacity. Although limited by the modest sample size, the semiquantitative nature of Western blot analyses, and the potential effect of medication exposure, this study supports the relevance of patient‐derived ONSPCs as a physiologically meaningful platform for investigating neurodevelopmental mechanisms underlying schizophrenia.