Functional characteristics of hub and wave-initiator cells in β cell networks

Abstract

Islets of Langerhans operate as multicellular networks in which several hundred β cells work in synchrony to produce secretory pulses of insulin, a hormone crucial for controlling metabolic homeostasis. Their collective rhythmic activity is facilitated by gap junctional coupling and affected by their functional heterogeneity, but the details of this robust and coordinated behavior are still not fully understood. Recent advances in multicellular imaging and optogenetic and photopharmacological strategies, as well as in network science, have led to the discovery of specialized β cell subpopulations that were suggested to critically determine the collective dynamics in the islets. In particular hubs, i.e., β cells with many functional connections, are believed to significantly enhance communication capacities of the intercellular network and facilitate an efficient spreading of intercellular Ca²⁺ waves, whereas wave-initiator cells trigger intercellular signals in their cohorts. Here, we determined Ca²⁺ signaling characteristics of these two β cell subpopulations and the relationship between them by means of functional multicellular Ca²⁺ imaging in mouse pancreatic tissue slices in combination with methods of complex network theory. We constructed network layers based on individual Ca²⁺ waves to identify wave initiators, and functional correlation-based networks to detect hubs. We found that both cell types exhibit a higher-than-average active time under both physiological and supraphysiological glucose concentrations, but also that they differ significantly in many other functional characteristics. Specifically, Ca²⁺ oscillations in hubs are more regular, and their role appears to be much more stable over time than for initiator cells. Moreover, in contrast to wave initiators, hubs transmit intercellular signals faster than other cells, which implies a stronger intercellular coupling. Our research indicates that hubs and wave-initiator cell subpopulations are both natural features of healthy pancreatic islets, but their functional roles in principle do not overlap and should thus not be considered equal.