Single cell transcriptomics of human epidermis identifies basal stem cell transition states

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.

Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells

“…Instead, our profiling refers to clonogenic cultured keratinocytes mimicking wound healing and epidermal regeneration. Despite this fundamental difference, similar clusters of basal keratinocytes have been identified in both conditions: the BAS-II cluster is similar to our H cluster and the BAS-I cluster is similar to our M cluster 45 . The notion that the BAS-II cluster contains more cells than BAS-I is consistent with the notion that, as opposed to primary cultures, single clonogenic keratinocytes directly analyzed from a skin biopsy generate more holoclones than meroclones 46 .…”

“…Very recently, single cell RNA-seq has been performed on keratinocytes directly isolated from skin biopsies, hence on a resting, mature epidermis 45 . Instead, our profiling refers to clonogenic cultured keratinocytes mimicking wound healing and epidermal regeneration.…”

An mTORC1-dependent switch orchestrates the transition between mouse spermatogonial stem cells and clones of progenitor spermatogonia

“…(G) Model positing that the transition between activated SSCs and clones of early progenitors is dependent upon mTORC1 activity. OPEN ACCESS (Zywitza et al, 2018;Wang et al, 2020;Xia et al, 2019;Bergen et al, 2020), including among human spermatogonia (Guo et al, 2018). More definitive confirmation of cell-state transitions at the resolution of SSC and progenitor subtypes would require future live imaging or genetic lineage tracing.…”

Defining compartmentalized stem cell populations with distinct cell division dynamics in the ocular surface epithelium

“…However, recent studies have challenged the universality of the hierarchical model, suggesting that the relationship between LRCs and their SC potential can be tissue- or context-dependent. In the interfollicular epidermis and oral epithelium, different epithelial compartments accommodate heterogeneous populations of SCs that show differences in cell division dynamics, location, molecular properties, biological functions and tumorigenic abilities ( Byrd et al, 2019 ; Füllgrabe et al, 2015 ; Gomez et al, 2013 ; Kretzschmar et al, 2016 ; Page et al, 2013 ; Roy et al, 2016 ; Sada et al, 2016 ; Sánchez-Danés et al, 2016 ; Wang et al, 2020 ). In contrast, the single population model suggests that epithelial tissues are maintained not by functionally discrete SC populations, but by a homogeneous population of SCs that undergoes stochastic divisions and fate choices ( Clayton et al, 2007 ; Doupé et al, 2012 , 2010 ; Jones et al, 2019 ; Krieger and Simons, 2015 ; Piedrafita et al, 2020 ; Rompolas et al, 2012 ).…”