The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Abstract

Adult tissues such as the epidermis of the skin and the epithelium lining the esophagus are continuously turned over throughout life. Cells are shed from the tissue surface and replaced by cell division. Yet, the cellular mechanisms that underpin these tissues homeostasis remain poorly established, having important implications for wound healing and carcinogenesis. Lineage tracing, in which of a cohort of proliferating cells and their descendants are genetically labelled in transgenic mice, has been used to study the fate behavior of the proliferating cells that maintain these tissues. However, based on this technique, distinct mutually irreconcilable models, differing in the implored number and hierarchy of proliferating cell types, have been proposed to explain homeostasis. To elucidate which of these conflicting scenarios should prevail, here we performed cell proliferation assays across multiple body sites in transgenic H2BGFP mouse epidermis and esophagus. Cell-cycle properties were then extracted from the H2BGFP dilution kinetics and adopted in a common analytic approach for a refined analysis of a new lineage-tracing experiment and eight published clonal data sets from esophagus and different skin territories. Our results show H2BGFP dilution profiles remained unimodal over time, indicating the absence of slow-cycling stem cells across all tissues analyzed. We find that despite using diverse genetic labelling approaches, all lineage-tracing data sets are consistent with tissues maintenance by a single population of proliferating cells. The outcome of a given division is unpredictable but, on average the likelihood of producing proliferating and differentiating cells is balanced, ensuring tissue homeostasis. The fate outcomes of sister cells are anticorrelated. We conclude a single cell population maintains squamous epithelial homeostasis.

A G1 Sizer Coordinates Growth and Division in the Mouse Epidermis

“…Cells cycled every 71 ± 21 h, with the majority of time spent in G1 phase ( Figures 2B-2D). This estimate is consistent with independent estimates of hindpaw cell-cycle durations [18]. Notably, cell cycles in vivo are much longer than cell cycles in vitro, where cell lines typically divide once a day.…”

A G1 sizer mechanism coordinates growth and division in the mouse epidermis

“…Cells on average cycled every 71 ± 21h (std), with the majority of time spent in G1 phase (Figure 2B-D). This estimate is consistent with independent estimates of hindpaw epidermis cell cycle durations [18]. Notably, cell cycles in vivo are much longer than cell cycles in vitro, where cell lines typically divide once a day.…”

Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues

“…A single cell population maintains squamous epithelial homeostasis in the oesophagus in the absence of slow-cycling stem cells 47 , 48 . This cell population is believed to reside in basal layers and maintains homeostasis by producing on average a daughter cell that replenishes the population and a daughter cell that continues to differentiate, thereby exiting the cell-cycle and moving up supra-basal layers.…”