A Single-Cell and Spatial Atlas of Early Human Olfactory Development

The human nasal region is a complex structure derived from neural crest and placodal lineages, but its development remains poorly understood due to limited fetal tissue access and its intricate architecture. To address this, we created a single-nucleus and spatial transcriptomic atlas of the human fetal nasal region using tissue from 10 fetuses between 7 and 12 post-conceptional weeks. Single-nucleus RNA sequencing (snRNA-seq) revealed 34 distinct cell types, including epithelial, cartilaginous, immune, neuronal, glial, muscular, and vascular cells. By integrating snRNA-seq with multiplexed error-robust fluorescence in situ hybridization (MERFISH), we tracked dynamic changes in cell composition and gene expression over time in the olfactory epithelium (OE) and surrounding nasal regions. We identified novel markers of olfactory sensory neuron development and key pathways regulating epithelial patterning and OE morphogenesis. Notably, we observed molecular signatures consistent with the "one neuron-one receptor" model already during the first trimester of development, with spatially organized expression of 171 olfactory receptor genes. Together, this study presents the first integrated molecular and spatial framework of early human olfactory development. It offers an unprecedented molecular blueprint of olfactory system formation and serves as a foundational resource for embryologists and developmental biologists studying sensory neurogenesis, epithelial patterning, and congenital disorders.