Human olfactory neuronal cells through nasal biopsy: molecular characterization and utility in brain science

Abstract

ABSTRACTBiopsy is crucial in clinical medicine to obtain tissues and cells that may directly reflect the pathological changes of each disease. However, the brain is an exception due to ethical and practical challenges. Nasal biopsy, which captures olfactory neurons and their progenitors, has been considered as an alternative method of obtaining neuronal cells from living patients. Multiple groups, including us, have enriched olfactory neuronal cells (ONCs) from nasal biopsied tissue. ONCs can be obtained from repeated biopsies in a longitudinal study, providing mechanistic insight associated with dynamic changes along the disease trajectory and treatment response. Nevertheless, molecular characterization of nasal biopsied cells/tissue has been insufficient. Taking advantage of recent advances in next-generation sequencing technologies at the single-cell resolution and related rich public databases, we aimed to define the neuronal characteristics of ONCs, their homogeneity, and their utility. We conducted single-cell and bulk RNA sequencing, analyzed and compared the data with multiple public datasets. We observed that the molecular signatures of ONCs are similar to those of neurons, distinct from major glial cells. The signatures of ONCs resemble those of developing neurons and share features of excitatory neurons in the prefrontal and cingulate cortex. The high homogeneity of ONCs is advantageous in pharmacological, functional, and protein studies. Together, the present data solidify the utility of ONCs in studying molecular mechanisms and exploring objective biomarkers for brain disorders. The ONCs may also be useful in studying the potential link between the olfactory epithelium impairment and the resultant mental dysfunction elicited by SARS-CoV-2.SIGNIFICANCE STATEMENTTo study dynamic changes and underlying mechanisms along disease trajectory and treatment response in neuropsychiatric disorders, olfactory neuronal cells (ONCs) enriched from nasal biopsied tissue may provide a crucial tool. Because ONCs can be obtained from repeated biopsies in a longitudinal study, this tool has been believed to be useful and complementary to postmortem brains and induced pluripotent stem cell-derived neurons. Nevertheless, molecular characterization of nasal biopsied cells/tissue has been insufficient, which hampers a wider use of this resource. Taking advantage of recent advances in next-generation sequencing technologies at the single-cell resolution and related rich public databases, the present study defines the neuronal characteristics of ONCs, their homogeneity, and their unique utility for the first time.