Several molecular markers have been described to predict stem cell potential with great success, e.g., in tissues like the blood, where a clear hierarchy of functional cell types can be identified. In other tissues, neutral competitive dynamics has been reported to remove a large fraction of biochemically identifiable stem cells, thereby creating a severe mismatch between cell-specific biochemical identity and the actual role of them as functional stem cells within the collective. In the case of the intestinal epithelium, this mismatch goes even further: In spite the number of biochemically identifiable (LGR5+) stem cells is the same in the crypts of both large and small intestines, lineage tracing techniques show that the number of them that actually play the role of stem cell displays remarkable differences. In that context, a natural question arises: How to determine the functional number and location of stem cells? To address this problem, I will revise a recent mathematical approach that proposes a new stem cell regulation mechanism, leading the final stem cell population to emerge only from the collective stochastic dynamics of cell movements and geometric considerations. Within this framework, one can accurately predict the robust emergence of a region made of functional stem cells and the actual number of them, as well as the lineage-survival probabilities, among other observables. The presented approach does not neglect the key role of biomarkers: Instead, it points towards the existence of complementary regulatory mechanisms --based on collective phenomena, stochastic dynamics and organ geometry--, playing an active role in determining the emergence and location of different cell functionalities.

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