Human keratinocytes have two interconvertible modes of proliferation

Abstract

SummarySingle stem cells, including those in human epidermis, have a remarkable ability to reconstitute tissues in vitro, but the cellular mechanisms that enable this are ill defined. We used live imaging to track the outcome of thousands of divisions in clonal cultures of primary human epidermal keratinocytes. Two modes of proliferation were seen. In ‘balanced’ mode, similar proportions of proliferating and differentiating cells were generated, achieving the ‘population asymmetry’ that sustains epidermal homeostasis in vivo. In ‘expanding’ mode, an excess of cycling cells was produced, generating large expanding colonies. Cells in expanding mode switched their behaviour to balanced mode once local confluence was attained. However when a confluent area is wounded in a scratch assay, cells near the scratch switch back to expanding mode until the defect is closed. We conclude that the ability of a single epidermal stem cell to reconstitute an epithelium is explained by two interconvertible modes of proliferation regulated by confluence.

Defining stem cell dynamics and migration during wound healing in mouse skin epidermis

“…6h), consistent with the majority of progenitors maintaining homoeostatic behaviour, leading to a progressive decrease in the labelled cell fraction125354. Importantly, this clonal dynamic contrasts with that reported for oesophagus, where repair seems to involve a switch of progenitors to a proliferative mode of division55, or following in vitro culture of human keratinocytes56. Consistent with a major increase in the rate of terminal differentiation, as measured by clonal persistence, the epidermal thickness increased during the same period (Fig.…”

Spatiotemporal coordination of stem cell commitment during epidermal homeostasis

“…This provides a foundation for future work to investigate the largely unknown regulatory mechanisms that coordinate cell-cell interactions on a tissue scale, during homeostasis. Furthermore, such progressive acquisition of cell fate could allow for cells in the epidermis to remain flexible in response to environmental demands, as was recently suggested from work on human keratinocytes in vitro (30), and therefore has potential relevance to pathological states and regeneration.…”

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

“…A subset of highy proliferative epidermal cells has the potential to generate large stratified colonies that subsequently fuse to form multi-layered cell sheets, recapitulating the organization of the epidermis9111213. This culture system has been widely used to study human epidermal SCs and their regulation1112131415, and epidermal sheets generated in vitro are used for autologous transplantation in patients suffering from severe burn wounds or hereditary skin blistering diseases1617. The grafted epidermal sheets can persist as a histologically and physiologically normal epidermis for years161718.…”

“…The grafted epidermal sheets can persist as a histologically and physiologically normal epidermis for years161718. However, due to the marked heterogeneity in the proliferative potential of individual primary human epidermal cells111213 engraftment of epidermal sheets after transplantation is highly unpredictable181920.…”