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Tissue stem cells are generated from a population of embryonic progenitors through organ-specific morphogenetic events1,2. Although tissue stem cells are central to organ homeostasis and regeneration, it remains unclear how they are induced during development, mainly because of the lack of markers that exclusively label prospective stem cells. Here we combine marker-independent long-term 3D live imaging and single-cell transcriptomics to capture a dynamic lineage progression and transcriptome changes in the entire epithelium of the mouse hair follicle as it develops. We found that the precursors of different epithelial lineages were aligned in a 2D concentric manner in the basal layer of the hair placode. Each concentric ring acquired unique transcriptomes and extended to form longitudinally aligned, 3D cylindrical compartments. Prospective bulge stem cells were derived from the peripheral ring of the placode basal layer, but not from suprabasal cells (as was previously suggested3). The fate of placode cells is determined by the cell position, rather than by the orientation of cell division. We also identified 13 gene clusters: the ensemble expression dynamics of these clusters drew the entire transcriptional landscape of epithelial lineage diversification, consistent with cell lineage data. Combining these findings with previous work on the development of appendages in insects4,5, we describe the 'telescope model', a generalized model for the development of ectodermal organs in which 2D concentric zones in the placode telescope out to form 3D longitudinally aligned cylindrical compartments.
Most ectodermal appendages, including hair follicles, form from the placode6. The hair placode elongates towards the dermis and develops into a cylindrical structure with longitudinally aligned compartments, one of which is the SOX9+ bulge stem cell compartment7,8. Previous studies have shown that SOX9+ suprabasal cells generated by the asymmetric division of basal epithelial cells of the placode become bulge stem cells1,3,9, which suggests that stem cells are first specified by asymmetric cell division. However, it remains unclear how the immature placode cells develop into the mature hair follicle structure and how organ-wide lineage diversification, including that of stem cells, is orchestrated at the cellular and transcriptional levels.
One major obstacle to studying the developmental origins of epithelial lineages is the lack of specific markers to enable the prospective identification and tracking of each cell lineage. Although basal epithelial cells in the...