Epithelial-mesenchymal Micro-niches Govern Stem Cell Lineage Choices

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Epithelial-Mesenchymal Micro-niches Govern Stem Cell Lineage Choices
Hanseul Yang, Rene C. Adam, Yejing Ge, Zhong L. Hua, Elaine Fuchs

Highlights

•Single-cell RNA-seq reveals heterogeneity within hair follicle progenitors and niches
•Heterogeneity is functionally required to build complex epithelia from the outside in
•Stem-cell plasticity becomes restricted in a spatio-temporally choreographed program
•Epithelial-mesenchymal micro-niches coordinate multi-lineage tissue growth

Summary
Adult tissue stem cells (SCs) reside in niches, which, through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single-cell RNA-seq, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage tracing, temporal single-cell analyses, and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged unilineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: some progenitors specify lineages immediately, whereas others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.

Keywords:

stem cells, epithelial-mesenchymal interactions, lineage determination, tissue regeneration, single-cell analyses

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