Cultured Mesenchymal Cells (CNON) as a Cellular Model to Study the Neurodevelopmental Component of Schizophrenia Etiology

Abstract

Schizophrenia (SCZ) is associated with alteration in brain development but the direct study of schizophrenia-related alterations in embryos and fetuses is not feasible. To address this, cell cultures from olfactory neuroepithelium (ON), where neurogenesis occurs throughout life, were utilized. As such, cell cultures from ON could serve as a model for studying neurodevelopmental processes. Recent advancements in single-cell RNA sequencing(scRNA-seq) have allowed for a precise characterization of their gene expression. Although these cells can differentiate into neurons and were previously characterized as neural progenitors (CNON), single-cell data analysis reveals that CNON’s expression profile differs from the gene expression profile of neural progenitors in olfactory epithelium (globose basal cells) and known neural progenitors in the human developing brain. Using scRNA-seq, CNON cells were characterized as mesenchymal stem cells (MSCs) based on their transcriptomes. CNON transcriptomes mapped to a distinct cluster in middle turbinate and olfactory epithelium samples, suggesting a singular cellular identity. MSCs are known for their role in supporting tissue regeneration. This led to the hypothesis that CNON cells are MSCs that play an important role in supporting neurodevelopment in the developing brain. Indeed, CNON cells express extracellular matrix proteins and multiple ligands that regulate neurodevelopment. Some of these genes are differentially expressed in cell lines derived from patients with schizophrenia, supporting the hypothesis that MSCs are involved in the etiology of the disease. To explore this further, the presence of these cells in the developing brain was investigated. The gene expression profile of CNON cells corresponded to a distinct cell type found in the developing brain, most profoundly present around weeks 5 to 6 of embryonic development. In summary, characterizing CNON cells aims to elucidate their role in neurodevelopment and establish their utility as a cellular model for investigating the cellular mechanisms of schizophrenia and other brain disorders