Cycling up the epidermis: reconciling 100 years of debate

Abstract

There is likely general consensus within the skin research community that cell cycle control is critical to epidermal homeostasis and disease. The current predominant model proposes that keratinocytes switch off DNA replication and undergo cell cycle and cell growth arrest as they initiate terminal differentiation. However, this model cannot explain key physiological features of the skin, mainly why squamous differentiation prevails over proliferation in benign hyperproliferative disorders. In recent years, we have proposed an alternative model that involves mitotic slippage and endoreplication. This new model is controversial and has encountered resistance within the field. However, looking back at history, the epidermal cell cycle has been a matter of controversy and debate for around 100 years now. The accumulated data are confusing and contradictory. Our present model can explain and reconcile both old and new paradoxical observations. Here, we explain and discuss the endoreplicative cell cycle, the evidence for and against its existence in human epidermis and the important implications for skin homeostasis and disease. We show that regardless of the strengths or weaknesses of the Endoreplication Model, the existing evidence in support of the Cell Cycle Arrest Model is very weak.

The EGF receptor ligand amphiregulin controls cell division via FoxM1

“…Thus, keratinocytes continue to replicate their DNA without equivalent execution of cell division as they differentiate, resulting in the production of large cells with increased DNA content as cells progress through the suprabasal layers. 2,64,65 In addition, the inhibition of mitotic kinases such as CDK1, Aurora kinase B, or PLK1 triggers polyploidization and differentiation of primary keratinocytes. 64,65 These published results are very consistent with our findings that in addition to producing binucleated cells with ≥4n DNA content (Figure 1), AREG silencing leads to the accumulation of flattened keratinocytes that are strongly engaged in terminal differentiation (Figure 2).…”

“…2 Epidermal growth factor receptor (EGFR) signaling is an important regulator of epidermal development and homeostasis 3–6 and plays an important role in the control of multiple keratinocyte functions including migration, 7,8 proliferation, 9 differentiation, 10–12 survival 13,14 and activation of innate and adaptive immune responses. 15–17 Deregulated EGFR signaling is a hallmark of epithelial cancer 18 , and EGFR is a validated target in several types of carcinomas.…”

When bigger is better: the role of polyploidy in organogenesis

“…In both mammals, there is a basal layer containing proliferative cells that give rise to keratinocytes. As the mitotic divisions from the basal layer push keratinocytes towards the surface of the skin, they differentiate and become polyploid by endomitosis or the endocycle (Figure 2C) [30–32]. The junctions between polyploid keratinocytes have not been analyzed, but the presence of large cells, possibly connected into an envelope, could protect the underlying tissue layers.…”

Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

“…It has been recently shown that an increase in ploidy due to a mitotic block is associated with terminal differentiation in human epidermis (Gandarillas and Freije, 2014; Zanet et al, 2010). Using fluorescence in situ hybridization (FISH) assays, we confirmed the presence of some polyploid cells in the suprabasal layers of mouse skin (Fig.…”

“…Several molecular mechanisms are instrumental for the control of the finely tuned balance between proliferation and differentiation, including genetic and epigenetic changes, transcriptional regulation, signalling cues and cellular interactions (Blanpain and Fuchs, 2009; Simpson et al, 2011). Moreover, recent reports show that a mitotic block coupled to an increase in ploidy is associated with epidermal differentiation (Gandarillas and Freije, 2014; Zanet et al, 2010). Indeed, a ploidy increase is linked to cell differentiation during the development of multiple organs (Lee et al, 2009; Orr-Weaver, 2015), but despite its relevance, the molecular mechanisms involved remain poorly characterized.…”