Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer

Abstract

The epidermis and skin appendages are maintained by their resident epithelial stem cells, which undergo long-term self-renewal and multilineage differentiation. Upon injury, stem cells are activated to mediate re-epithelialization and restore tissue function. During this process, they often mount lineage plasticity and expand their fates in response to damage signals. Stem cell function is tightly controlled by transcription machineries and signalling transductions, many of which derail in degenerative, inflammatory and malignant dermatologic diseases. Here, by describing both well-characterized and newly emerged pathways, we discuss the transcriptional and signalling mechanisms governing skin epithelial homeostasis, wound repair and squamous cancer. Throughout, we highlight common themes underscoring epithelial stem cell plasticity and tissue-level crosstalk in the context of skin physiology and pathology.

Keywords: cutaneous squamous cell carcinomas; epigenetic regulators; lineage plasticity; signalling transduction; skin epithelial stem cells; transcription factors.

FIGURE 1

Squamous lineage transcription factors (TFs) control skin epithelia form, function and diseases. (A) The stratified skin epidermis is composed of several epithelial layers, including the basal layer, harbouring epidermal stem cells (EpdSCs), suprabasal spinous and granular layers, and the stratum corneum (left). Skin blistering diseases occur when the epidermal adhesions and junctions are compromised, and barrier defects originate from disruptions of the stratification programme, including genes of cross-linking enzymes, cornified envelop and lipid metabolism. A common non-melanoma skin cancer, cutaneous squamous cell carcinoma (cSCC), arises from the skin epithelium and mimics wounds that never heal. (B) p63 maintains EpdSC proliferation and prevents precocious stratification by antagonizing p53, cell cycle inhibitors, 14-3-3σ, Notch, IKKα and activating miR-205. (C) p63 also regulates the expression of many cell adhesion and junction components, including Perp (desmosome), claudin (tight junction), keratins (intermediate filaments), integrins (adherens junctions), laminins (basement membrane), and Fras1 and Frem1/2 (extracellular matrix). (D) Squamous lineage TFs are p63 targets and join p63 to regulate epidermal stratification; many of these TFs are deregulated in congenital ectodermal conditions and skin inflammatory and malignant diseases

FIGURE 2

Growth and stress signalling pathways dictate responsiveness to stimuli and are hijacked in skin malignancy. (A) ETS family TFs are phosphorylated by the RAS MAPK pathway, downstream of receptor tyrosine kinase (RTK) signalling, for example EGF/EGFR and FGF/FGFR. ETS is also stimulated by ultraviolet light and TPA exposure. Targets of ETS TFs include stratification genes (cross-linking enzymes, cornified envelop, lipid metabolism), cell cycle (MYC, Cyclin D1, P16, TGFBR2), apoptosis (MDM2, BAX, BCL2), matrix metalloproteases (MMPs) and cytokine/chemokine genes (IL-8, TNF-α). (B) AP-1 TFs are the principal effector TFs of TPA signalling. AP-1 is also activated by serum, growth factors and JNK signalling, and shares some common effectors with calcium signalling, such as protein kinase C (PKC). AP-1 induces stratification, matrix remodelling (collagenase, MMPs, uPA, TIMP3) and inflammation (COX2, S100), among others. uPA, urokinase-type plasminogen activator. (C) Notch receptor binds its ligands (DLL1, JAG1/2) in a juxtacrine or autocrine fashion and is activated by two consecutive protease activities (TACE, γ-secretase), resulting in activation of HES1, p21 and stratification genes and repression of p63 and WNT4. TACE, tumor necrosis factor-alpha–converting enzyme, also known as ADAM17 (ADAM metallopeptidase domain 17). NICD, notch intracellular domain. (D) NF-κB signalling has several skin-specific functions: EDA/EDAR regulates hair follicle (HF) specification, ultraviolet light activates TRAF2, IKKα regulates squamous stratification, and NF-κB functions as a tumor suppressor promoting epidermal differentiation. NF-κB is also activated by TPA and calcium, and its downstream targets include stratification, survival (Bcl-x, c-FLIP), inflammatory enzymes (COX2), matrix remodelling (MMPs), cytokines/chemokines (TNF-α, IL-1, IL-6, GM-CSF, IL-8, KC, MIP2) and angiogenesis (VEGF)

FIGURE 3

Cooperation of squamous, stress and epigenetic regulators in driving skin epithelial stem cell plasticity. (A) TFs such as p63 are regulated at multiple levels, including post-translational modifications by phosphorylation and ubiquitination, post-transcriptional regulation by miRNAs, alternative splicing and positive feedback regulations. (B) A group of TFs govern hair follicle stem cell (HFSC) quiescence, including SOX9, LHX2, TCF3, TCF4, NFATC1 and FOXC1, while KLF5 is specifically enriched in EpdSCs. Upon wounding, HFSCs induce the expression of KLF5, which is coexpressed with SOX9, ETS2, AP-1 and p63, among others, resulting in stem cell lineage infidelity, an epigenetically rewired state that is functionally required for wound repair. (C) Several groups of epigenetic factors are integrated in the regulation of EpdSC proliferation (P) and differentiation (D), including histone deacetylases (HDAC1/2, HDAC3), histone methyltransferases, demethylases, and their regulators (EZH2, CBX4, KMT2C/D, KMT4A, KMT6B), chromatin remodelers (BRG1, SATB1, ACTL6A), and DNA methyltransferases and regulators (DNMT1, DNMT3A/B, UHRF1). KMT2C is also known as MLL3, KMT2D as MLL2, KDM4A as JMJD2, and KDM6B as JMJD3. The hypothetical epigenetic factor is depicted arbitrarily with multiple activities