Reconstruction of a Pancreatic Beta Cell Network From Heterogeneous Functional Measurements

Intercellular heterogeneity is fundamental to most biological tissues. For some cell types, heterogeneity is thought to be responsible for distinct cellular phenotypes and functional roles. In the pancreatic islet, subsets of phenotypically distinct beta cells (hub and leader cells) are thought to coordinate electrical activity of the beta cell network. This hypothesis has been addressed by experimental and computational approaches, but none have attempted to reconstruct functional specialization directly from measured heterogeneity. To evaluate if electrophysiologic heterogeneity alone can explain these specialized functional roles, we created a population of human beta cell models (via genetic algorithm optimization) recapitulating the heterogeneity in an extensive patch clamp dataset (1021 pancreatic cells). Then we applied the simplified Kirchhoff network (SKNM) formalism to simulate activity of that population in a connected beta cell network. We could not immediately observe cells with obvious hub or leader phenotypes within the heterogeneous network. However, with this study we built the basis for further ”ground-up” investigation of relationships between beta cell heterogeneity and human islet function. Moreover, our workflow may be translated to other tissues where large electrophysiologic data sets become available, and heterogeneity is thought to influence tissue function e.g. human atria.