Abstract
How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling suggests that basal cell populations serve as crucial signaling hubs to maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest that transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.
Highlights
How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation
Each population is spatially distinct, with Basal Type III - (BAS-III) cells occupying space between rete ridges and BASIV residing at the tips or bottom of the rete ridges, whereas the Basal Type I - (BAS-I) and Basal Type II - (BAS-II) populations showing sparse and heterogenous distribution throughout the basal and suprabasal layers
Analyzing cell-cell communication, gene profile dynamics, and genetic loss-of-function experiments indicate that the WNT target gene and epigenetic modifiers UHRF1 and HELLS and the protooncogene PTTG1 are essential for epidermal homeostasis
Summary
How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. We use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. ScRNA-seq has identified extensive functional heterogeneity in skin[16,17,18,19], hair follicles[20,21], and regenerative and nonregenerative wounds[22,23] Despite these studies, epidermal SC heterogeneity of human IFE remains unresolved. Epidermal SC heterogeneity of human IFE remains unresolved To address this issue, we interrogate epidermal cell heterogeneity within human neonatal foreskin epidermis using droplet-enabled scRNA-seq and identify four spatially distinct basal SC subpopulations. Our findings argue against a single population of progenitor cells and suggest a more complex model of multiple epidermal SC transitions that maintain epidermal homeostasis
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