Deconstructing Olfactory Stem Cell Trajectories at Single-Cell Resolution

A detailed understanding of the paths that stem cells traverse to generate mature progeny is vital for elucidating the mechanisms governing cell fate decisions and tissue homeostasis. Adult stem cells maintain and regenerate multiple mature cell lineages in the olfactory epithelium. Here we integrate single-cell RNA sequencing and robust statistical analyses with in vivo lineage tracing to define a detailed map of the postnatal olfactory epithelium, revealing cell fate potentials and branchpoints in olfactory stem cell lineage trajectories. Olfactory stem cells produce support cells via direct fate conversion in the absence of cell division, and their multipotency at the population level reflects collective unipotent cell fate decisions by single stem cells. We further demonstrate that Wnt signaling regulates stem cell fate by promoting neuronal fate choices. This integrated approach reveals the mechanisms guiding olfactory lineage trajectories and provides a model for deconstructing similar hierarchies in other stem cell niches. The olfactory epithelium is a site of active neurogenesis. Fletcher et al. combine single-cell transcriptomics and clonal lineage analysis to trace cell fates from the multipotent olfactory stem cell and identify multiple mechanisms controlling cell fate, including direct conversion of quiescent stem cells into support cells without cell division.