Dimensionality and Calcium Dynamics in Pancreatic β-Cell Clusters

Abstract

The pancreatic islet is a multicellular organ which provides the sole source of insulin for regulating blood glucose levels. Thus, a functional understanding of the islet is of critical importance to effectively treat diabetes. Beta cells within native islets produce large bursts of insulin to meet physiological needs by mounting a coordinated electrophysiological response. However, when removed from their native three dimensional (3D) environment, they lose much of their coordination and responsiveness. This observation draws parallels with the hindered diabetic response and emphasizes the importance of understanding the electrical dynamics that underlie the coordinated pulsatile secretion of insulin.In this work, we use quantitative microscopy to measure intra-cellular free calcium activity ([Ca2+]i) and coordination of β-cells in 1D, 2D and 3D clusters. using a novel method of aggregating β-cells back into 3D systems, we can provide a better model for understanding the effects of dimensionality and coupling on ([Ca2+]i) dynamics. We have found that by re-aggregating β-cells, they return to a native-like oscillatory behavior, which is lost in 2D cultures. In addition, the overall coordination of 2D clusters was found to decrease with cluster size, showing distinct sub-regions of coordination, while the 3D cultures were better coordinated at comparable sizes and cell numbers.Using a percolation-based theory for modeling cell coordination, we show how higher dimensions of coupling lead to better overall synchrony with larger regions of coordination. This model also predicts the distances over which coupled cells can communicate. This has broader implications in that a loss of cell coupling and a reduction in coordination and responsiveness are often seen in islets from models of type2 diabetes. Also, the application of our mathematical model to predict cellular phenomena yields new insight in understanding the coordinated behavior of electrophysiological signaling in general.