Abstract
Using in-vivo lineage tracing data we quantified clonal expansion as well as proliferation and differentiation of the Lgr5-positive stem cell population in pyloric gastric glands. Fitting clone expansion models, we estimated that there are five effective Lgr5-positive cells able to give rise to monoclonal glands by replacing each other following a pattern of neutral drift dynamics. This analysis is instrumental to assess stem cell performance; however, stem cell proliferation is not quantified by clone expansion analysis. We identified a suitable mathematical model to quantify proliferation and differentiation of the Lgr5-positive population. As expected for populations in steady-state, the proliferation rate of the Lgr5-positive population was equal to its rate of differentiation. This rate was significantly faster than the rate at which effective cells are replaced, estimated by modelling clone expansion/contraction. This suggests that the majority of Lgr5-positive cell divisions serve to renew epithelial cells and only few result in the effective replacement of a neighbour to effect expansion to the entire gland. The application of the model under altered situations with uncoupled differentiation and proliferation was demonstrated. This methodology represents a valuable tool for quantifying stem cell performance in homeostasis and importantly for deciphering altered stem cell behaviour in disease.
Highlights
Using in-vivo lineage tracing data we quantified clonal expansion as well as proliferation and differentiation of the Lgr5-positive stem cell population in pyloric gastric glands
Mathematical modelling of the monoclonal expansion of stem cells based on lineage tracing datasets has been instrumental in demonstrating that small intestinal epithelial stem cells are equipotent with respect to their ability to populate the entire gland, typically divide symmetrically and are replaced at random according to a neutral drift pattern[8]
Using clonal expansion analysis we have identified 5 effective Lgr5-positive cells at the base able to expand to the entire gland; clones involving these 5 cells lose and gain 0.02 cells per day by random replacement
Summary
Using in-vivo lineage tracing data we quantified clonal expansion as well as proliferation and differentiation of the Lgr5-positive stem cell population in pyloric gastric glands. We estimated that there are five effective Lgr5-positive cells able to give rise to monoclonal glands by replacing each other following a pattern of neutral drift dynamics. This analysis is instrumental to assess stem cell performance; stem cell proliferation is not quantified by clone expansion analysis. Mathematical modelling of the monoclonal expansion of stem cells based on lineage tracing datasets has been instrumental in demonstrating that small intestinal epithelial stem cells are equipotent with respect to their ability to populate the entire gland, typically divide symmetrically and are replaced at random according to a neutral drift pattern[8]. These models have been adopted for the study of cell clonal expansion in colonic human epithelium based on the ribbon width of the clonal imprints derived from somatic mtDNA mutations[13]
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