Single-Cell RNA Profiling of Human Skin Reveals Age-Related Loss of Dermal Sheath Cells and Their Contribution to a Juvenile Phenotype

Abstract

The dermal sheath (DS) is a population of mesenchyme-derived skin cells with emerging importance for skin homeostasis. The DS includes hair follicle dermal stem cells, which exhibit self-renewal and serve as bipotent progenitors of dermal papilla (DP) cells and DS cells. Upon aging, stem cells exhibit deficiencies in self-renewal and their number is reduced. While the DS of mice has been examined in considerable detail, our knowledge of the human DS, the pathways contributing to its self-renewal and differentiation capacity and potential paracrine effects important for tissue regeneration and aging is very limited. Using single-cell RNA sequencing of human skin biopsies from donors of different ages we have now analyzed the transcriptome of 72,048 cells, including 50,149 fibroblasts. Our results show that DS cells that exhibit stem cell characteristics were lost upon aging. We further show that HES1, COL11A1, MYL4 and CTNNB1 regulate DS stem cell characteristics. Finally, the DS secreted protein Activin A showed paracrine effects on keratinocytes and dermal fibroblasts, promoting proliferation, epidermal thickness and pro-collagen production. Our work provides a detailed description of human DS identity on the single-cell level, its loss upon aging, its stem cell characteristics and its contribution to a juvenile skin phenotype.

Intercellular crosstalk in adult dental pulp is mediated by heparin-binding growth factors Pleiotrophin and Midkine

“…Other cells identified included immune cells (cluster 8, 13, 15, 1, and 14), endothelial cells (clusters 6 and 12), epithelial cells and keratinocytes (cluster 16). Finally, two clusters (5 and 10) with markers compatible with perivascular cells ( CSPG4 ) [ 12 ], including vascular smooth muscle cells ( ACTA2 , TAGLN , and TPM2 ) [ 13 , 14 ], and mesenchymal stem cells ( ACTA2 , FRZB , NOTCH3 , and MYH11 ) [ 6 , 12 ] were annotated as MSC-like cells (Supplementary Fig. 4 ).…”

Intercellular crosstalk in adult dental pulp is mediated by heparin-binding growth factors Pleiotrophin and Midkine

“…Other cells identified included immune cells (cluster 8, 13, 15, 1, and 14), endothelial cells (clusters 6 and 12), epithelial cells and keratinocytes (cluster 16). Finally, two clusters (5 and 10) with markers compatible with perivascular cells (CSPG4) (27), including vascular smooth muscle cells (ACTA2, TAGLN, and TPM2) (12,28), and mesenchymal stem cells (ACTA2, FRZB, NOTCH3, and MYH11) (9,27) were annotated as MSC-like cells ( Supplementary Fig 4 ).…”

“…FASTQ files of single-cell RNA sequencing (scRNA-seq) data were retrieved from published studies (2,(9)(10)(11)(12)(13). The data were selected based on healthy human tissue.…”

In vitro models for investigating itch

“…Ideally, human primary ex vivo tissue would provide the second-best option to human in vivo experiments for studying human chronic itch. Skin biopsies are highly accessible and include all itch relevant tissue-resident cells, as demonstrated by single cell sequencing experiments ( He et al, 2020 ; Ahlers et al, 2021 ). However, the main itch-sensing cells are sensory neurons, and their cell bodies are located in the DRG next to the spinal cord, which cannot be obtained from healthy living donors, although extraction of viable cells can be achieved under certain conditions when donors are deceased or undergoing certain surgery ( Valtcheva et al, 2016 ).…”