A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice

Abstract

In adult skin epidermis and the epithelium lining the esophagus cells are constantly shed from the tissue surface and replaced by cell division. Tracking genetically labelled cells in transgenic mice has given insight into cell behavior, but conflicting models appear consistent with the results. Here, we use an additional transgenic assay to follow cell division in mouse esophagus and the epidermis at multiple body sites. We find that proliferating cells divide at a similar rate, and place bounds on the distribution cell cycle times. By including these results in a common analytic approach, we show that data from eight lineage tracing experiments is consistent with tissue maintenance by a single population of proliferating cells. The outcome of a given cell division is unpredictable but, on average, the likelihood of producing proliferating and differentiating cells is equal, ensuring cellular homeostasis. These findings are key to understanding squamous epithelial homeostasis and carcinogenesis.

Methods for analysing lineage tracing datasets

“…This probability can be calculated using a published analytical solution of the branching process describing the single progenitor model (5). This however assumes that cell cycle times are exponentially distributed, which is not the case and can undermine this analysis (6). In this situation, bespoke simulation tools need to be run with extremely high sampling (over one-hundred thousand simulations per parameter combination) in order to calculate the clone size probability distributions accurately, at substantial computational cost.…”

“…Furthermore, a known issue of the analytical solution is the assumption of an exponential distribution of stem cell cycle times. Both histone dilution and live imaging experiments on epithelial tissues have shown that there is a refractory period in which no division can occur (6,7). This can undermine the analysis leading to the identification of incorrect parameters (6).…”

“…Both histone dilution and live imaging experiments on epithelial tissues have shown that there is a refractory period in which no division can occur (6,7). This can undermine the analysis leading to the identification of incorrect parameters (6). The issue in assuming an underlying exponentially distributed cell cycle time is also highlighted in the obtained clone size distributions at early time points,…”

“…Where the analysis allowed, we took account of the shape of the gamma distribution. This can be inferred through an orthogonal experimental protocol and so was not fit alongside other parameters (6).…”

Mutations in Non-Tumoral Human Urothelium: Disease Prelude or Epilogue?

“…"Clonal health" has been proposed as a homeostatic property of tissues that defines a healthy interaction among clonal populations inside the tissue [13]. Understanding the paradigms of proliferation and self-renewal and the forces that constrain mutant clone interactions in the urothelium could help to define clonal health status and how this property is lost in disease [14,15].…”