Keywords: Stochastic modelling; Lineage tracing; Pancreas dynamics.

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The cellular structure of the pancreas is quite well known, with the main components being a ductal structure throughout the whole pancreas and compartments of acinar cells (acini) connected to the endpoints of these ducts comprising about 95% of the pancreas. However, the exact mechanisms of homeostasis of the pancreas are yet unknown. In particular, it is heavily debated whether homeostasis is maintained by a stem cell compartment or equal participation of all acinar cells. Multiple studies have been published on this subject, but the employed lineage tracing methods are subject to bias, and thus far no mathematical models have been constructed to compare different possible dynamics of homeostasis. We aimed to employ a bias-free lineage tracing method to test which mechanism is responsible for tissue homeostasis.

We employed a lineage tracing strategy that was before used in the colon (Kozar et al., 2013) to stochastically mark proliferating cells. Each cell division has a chance of marking the dividing cell and all of its offspring. Using this method, clone size distributions over time in 55 mice ranging from 16-758 days of age were generated. These data were used to validate the accompanying models for tissue homeostasis.

To mathematically models the dynamics of the acinar pancreas, we employed a Moran-like model for the dynamics within an acinus. In this model, each acinus contains a set number of cells which was determined experimentally. Acini could interact with one another through fission-like events. The number of progenitor cells within an acinus was considered to be the parameter that defines the dynamics of the pancreas: a low number of progenitor cells implies the presence of a stem cell population whereas a high number of progenitor cells imply a uniform potential of proliferation across all acinar cells. We then performed a grid search to find the best values for the rates of cell division and acinus fission for each possible value of the number of progenitor cells. Results showed that the best fit was for a high number of progenitor cells per acinus, which also corresponded better to validations of other parameters in the model. This implies that each cell in the acinar pancreas has equal probability of contributing to tissue homeostasis.

The same model was used in a group of mice that were subjected to pancreatitis. Comparisons of clone size distributions before and after pancreatitis in this group showed that regeneration of the pancreas is likely lead by an accelerated rate of acinar fission-like events.

This research sheds light of the mechanisms of homeostasis in the pancreas, which is of importance for many diseases affecting the pancreas as diabetes and pancreatic cancer.

Lodestijn, S.C., Bosch, T. van den, Nijman, L.E., Moreno, L.F., Schlingemann, S., Sheraton, V.M., Neerven, S.M. van, Koning, J.J., Vieira Braga, F.A., Paauw, N.J., Lecca, M.C., Lenos, K.J., Morrissey, E., Miedema, D.M., Winton, D.J., Bijlsma, M.F., Vermeulen, L. (2021) Cell Stem Cell, Volume 28, Issue 11, 4 November 2021, P. 2009-2019 https://doi.org/10.1016/j.stem.2021.07.004