Mathematical Modeling of Beta Cell Turnover Reveals Non-Trivial Contributions of Apoptosis to Pancreas Development

Organ development is a fundamental process orchestrated by a balanced rate of proliferation and apoptosis. In stark contrast to proliferation, the relative contribution of apoptosis remains largely unexplored due to difficulties in its histological detection. Here, using a combinatorial approach of zebrafish genetics and mathematical modeling, we uncover a previously unrecognized role of apoptosis in pancreas development. Using systems of ordinary differential equations, stochastic formulations, and agent-based simulations, we show that apoptosis can be incorporated as a time- and context-dependent variable influencing net beta cell turnover. The model enabled precise quantification of apoptotic rates, delineation of the temporal onset of beta cell apoptosis, and prediction of beta cell mass in the absence of apoptosis. Taken together, the model enhances our understanding of apoptosis, its role in regulating beta cell mass, and its immunological implications. In the future, the model can be extended to study regenerative and cancer biology, providing insights into the consequences of abnormal cell death and supporting the design of therapeutic interventions. Akhtar MN, et al. Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk. EMBO J. 2025 Feb;44(4):1131-1153. doi: 10.1038/s44318-024-00332-w. Epub 2025 Jan 6. PMID: 39762647; PMCID: PMC11833124. https://www.embopress.org/doi/full/10.1038/s44318-024-00332-w