The Ordered Architecture of Murine Ear Epidermis Is Maintained by Progenitor Cells with Random Fate

Abstract

Typical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis.

Development and Homeostasis of the Skin Epidermis

“…According to this model, epidermal homeostasis is maintained by a combination of symmetric and asymmetric cell divisions; the majority of divisions are asymmetric and progenitors divide every 6-7 d. Using the same strategy of clonal analysis, it has been proposed that the ear epidermis is also maintained by one type of progenitor that randomly chooses between two fates, although the parameters of the cell cycle and the probability to self-renew and differentiate were different (Doupe et al 2010). Although these data challenge our current view of hierarchical homeostasis, it remains to be shown that the cells targeted in these studies are not a particular subpopulation of epidermal cells.…”

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

“…Later, quantitative lineage tracing studies based on inducible genetic labeling revealed that murine epidermal maintenance relies instead upon the turnover of a basal progenitor pool that conforms to a process of "population asymmetry" in which their stochastic loss through terminal division is perfectly compensated by the duplication of neighbors (27)(28)(29)(30) (Fig. 1B).…”

“…The resolution of cell fate behavior in mouse IFE relied upon the observation of "scaling" behavior of the clone size distribution following genetic pulse labeling (27)(28)(29)(30)35). According to their stochastic fate behavior (Fig.…”

Mutation, clonal fitness and field change in epithelial carcinogenesis

“…Both tissues are maintained by single populations of functionally equivalent progenitor cells [9][10][11]13,15]. As in the intestine, progenitor cell division is linked with the migration of a nearby differentiating cell out of the basal layer.…”

“…An important insight has been that clone size distributions at multiple time points can be used to generate simple quantitative models that capture the average behaviour of proliferating cells in homeostatic tissue [6,9]. This approach has since been applied in a series of studies in the epidermis, oesophagus, and intestine [10][11][12][13][14][15]. A recent development has been in vivo video imaging techniques, which complement the long-term lineage data with direct visualization of the behaviour of individual cells over a few rounds of cell division [16,17].…”