Skin Cell Heterogeneity in Development, Wound Healing, and Cancer

Abstract

Skin architecture and function depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, it is now recognised that there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss recent insights into how these distinct cell populations are maintained and coordinated during development, homeostasis, and wound healing. We highlight the importance of the local environment, or niche, in cellular plasticity. We also discuss new mechanisms that have been identified as influencing wound repair and cancer progression.

Keywords: fibroblast lineages; microniches; skin cancer; stem cell plasticity; wound healing.

Figure 1

Stem Cell and Mesenchymal Cell Population Diversity in the Skin. (A) Stem cell and other cell populations in the interfollicular epidermis and hair follicle. Distinct markers shown in the colour code legend have been identified mapping the spatial distribution of distinct stem cell and differentiated cell populations in the hair follicle bulge, isthmus, infundibulum, sebaceous gland, and interfollicular epidermis. A basement membrane separates the epidermis from the dermis. Note that the sebacous duct is not visible. (B) Mesenchymal cell populations in the indicated dermal layer. Papillary fibroblasts are located close to the basement membrane and surrounded by thin collagen fibres whereas reticular fibroblasts reside in the central dermis associated with thick collagen bundles (grey). The preadipocytes are located close to the DWAT, which harbours the mature, lipid-filled adipocytes. In addition, the dermis contains specialized fibroblast subpopulations (brown) forming the DP, DS, and APM, as well as surrounding the blood vessels (pericytes). Abbreviations: APM, arrector pili muscle; DP, dermal papilla; DS, dermal sheath; DWAT, dermal white adipose tissue; ECM, extracellular matrix; Lrig1, leucine-rich repeats and immunoglobulin-like domains protein 1.

Figure I

Comparison of Extrinsic and Intrinsic Regulatory Factors of Epithelial and Mesenchymal Cells in the Skin. Note that the arrow type and thickness indicates differential impact of extrinsic (orange) and intrinsic (blue) factors on epithelial (left) and mesenchymal (right) cells. Niche factors have been shown to exert a strong impact on all cell populations (solid thick arrow), impact on some cell populations (solid thin arrow), or weak/unclear/unknown impact (dashed thin arrow). A combination of extrinsic and intrinsic niche factors (black) defines the autocrine and epithelial/mesenchymal signals. Cell–cell interactions are categorised as homotypic (between neighbouring cells of the same type) and heterotypic (between other cell types such as immune, endothelial, or neuronal cells). Physical factors include tension, compression, shear stress, as well as temperature. Gene and chromatin refer to intrinsic changes in gene expression and chromatin state. Abbreviations: ECM, extracellular matrix; GF, growth factor.

Figure 2

Epidermal and Mesenchymal Cell Heterogeneity and Plasticity During Wound Healing. (A) Stem cells and other cell subpopulations are recruited during wound healing in the epidermis and dermis. While cell lineages of the bulge (brown), infundibulum (orange), and interfollicular epidermis (white) enter more as a cohesive cell population (solid arrows), sebaceous duct cells (blue) migrate to the wound site suprabasally as individual cells (dashed arrow) (1). Note that once different cells of the hair follicle and interfollicular epidermis enter the wound healing zones they exhibit similar cellular behaviours in proliferation (2) and cell migration and differentiation (3). Wound healing zone key features are shown in boxes,with cell division in the proliferative zone (2) and cell migration and differentiation in the migratory and differentiation zone (3). In the mixed zone all key features can be observed. Whether these zones of collective behaviour propagate into the dermis and how mesenchymal cells are organised during wound healing are less clear. During wound healing reticular fibroblasts (red) are the first and most abundant fibroblasts to enter the wound bed (red thick arrow) and are the major source of myofibroblasts (white cell in the wound bed). Papillary fibroblasts (green) enter the wound bed at a later stage (green thin arrow). Preadipocytes (yellow), adipocytes and pericytes (brown) have also been shown to contribute to dermal wound healing (black thin arrow). (B) Plasticity of epithelial cells during wound healing, with associated key signalling pathways and transcription factors. Epithelial cell populations of the interfollicular epidermis and hair follicle transiently lose their lineage identity during wound healing (central cell with red nucleus) and are able to differentiate (black arrow) or dedifferentiate (grey arrow) and acquire the potential to regenerate all tissue structures. (C) Plasticity of mesenchymal cells during wound healing with associated key signalling pathways. Mesenchymal cells close to the wound bed become activated (grey arrow), are referred to as myofibroblasts, and change their behaviour and transcriptional programme (central cell with red nucleus). Whether APM fibroblasts also participate is unknown (dashed grey arrow). During the wound resolution phase myofibroblasts are able to convert to adipocytes, interfollicular fibroblasts (solid black arrow) and presumably also other cell populations (dashed black arrow). Abbreviations: APM, arrector pili muscle; BMP, bone morphogenetic protein; MAPK, mitogen-activated protein kinase; TGFβ, transforming growth factor β.

Figure 3

Epidermal and Mesenchymal Cell Heterogeneity in Cancer. Distinct epithelial cell populations give rise to different tumour types. Oncogenic β-catenin signalling in different hair follicle stem cell populations of the bulge (CD34/Krt15⁺, pink; Gli1⁺, green; Lgr5⁺, violet, and Lgr6⁺, dark blue) and isthmus junctional zone (Lirg1⁺, orange) induce different types of benign hair follicle tumours (grey circle), while BCCs only arise from basal (Krt14⁺) interfollicular epidermis (white cell) and Lrig1⁺ cells of the hair follicle isthmus and infundibulum (orange cell) upon Hedgehog signalling activation (dark grey circle). In contrast, a hyperactive Kras mutation is able to induce SCC in all epidermal lineages (light grey circle). If different tumour types are associated with distinct mesenchymal subpopulations (green, papillary fibroblast; red, reticular fibroblast; yellow, preadipocyte; white, undefined fibroblast; brown, APM, dermal sheath, dermal papilla fibroblast, pericyte and adipocyte) (dashed arrows) and if mesenchymal subpopulation specific signalling pathways are involved (?), is unclear. Abbreviations: APM, arrector pili muscle; BCC, basal cell carcinoma; HF, hair follicle; SCC, squamous cell carcinoma.