Flipping the switch on the hub cell: Islet desynchronization through cell silencing

Abstract

Pancreatic β cells, responsible for secreting insulin into the bloodstream and maintaining glucose homeostasis, are organized in the islets of Langerhans as clusters of electrically coupled cells. Gap junctions, connecting neighboring cells, coordinate the behavior of the islet, leading to the synchronized oscillations in the intracellular calcium and insulin secretion in healthy islets. Recent experimental work has shown that silencing special hub cells can lead to a disruption in the coordinated behavior, calling into question the democratic paradigm of islet insulin secretion with more or less equal input from each β cell. Islets were shown to have scale-free functional connectivity and a hub cell whose silencing would lead to a loss of functional connectivity and activity in the islet. A mechanistic model representing the electrical and calcium dynamics of β cells during insulin secretion was applied to a network of cells connected by gap junctions to test the hypothesis of hub cells. Functional connectivity networks were built from the simulated calcium traces, with some networks classified as scale-free, confirming experimental results. Potential hub cells were identified using previously defined centrality measures, but silencing them was unable to desynchronize the islet. Instead, switch cells, which were able to turn off the activity of the islet but were not highly functionally connected, were found via systematically silencing each cell in the network.

From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science

“…At present, these findings cannot be completely reconciled with electrophysiological and modelling findings, for reasons that arguably originate in different methodological approaches [for a recent review see ( 60 )]. Our current understanding suggests that in a system of coupled cells of which all are intrinsically able to oscillate, silencing a small proportion of cells with the highest number of functional connections cannot prevent or importantly change the activity of the remaining cells, except close to the threshold for stimulation where the majority of cells would otherwise not be active by themselves ( 60 , 143 , 148 , 149 ). Further experiments in a near-threshold glucose milieu with ablation of hub cells rather than their silencing may further aid to our understanding of the role of hub cells in the islet syncytium.…”

“…The existence of hub cells was also linked with metabolic profiles, which will be addressed in more detail in section 5. The presence of long-range connections that give rise to small-world characteristics was attributed to various reasons associated with a complex multicellular dynamics, whereby heterogeneity and a heterogeneous coupling were highlighted also in theoretical models ( 142 , 143 ).…”

“…Several studies have utilized computational models to investigate how intercellular coupling facilitates beta cell synchronization ( 138 , 202 – 206 ) and the propagation of [Ca 2+ ] IC waves ( 74 , 207 , 208 ). In recent years, specific attention has been given to cellular heterogeneity and to how the collective activity emerges from functionally heterogeneous beta cell subpopulations ( 71 , 143 , 145 , 147 , 148 , 165 , 169 , 209 ). In the context of complex beta cell networks, it has been demonstrated that the coupling scheme between the beta cells represents the basis for the functional connectivity patterns, but the relation relies heavily on various physiological determinants, such as the level of stimulation, cellular noise, and the coupling parameters ( 210 ).…”

“…Multicellular models have also been employed to study the occurrence of long-range connections in functional beta cell networks. Importantly, it has been demonstrated that long-range synchronicity can in principle be established solely by the propagation of excitation waves through nearest-neighbor-coupled networks, if the cells and the coupling strengths are heterogeneous ( 142 , 143 , 211 ). In recent years, particular emphasis has also been given to the role of functional subpopulations, such as hubs and pacemaker cells, although their exact roles remain somewhat debatable.…”

“…Furthermore, by silencing a few hub cells within the islet it was possible in principle to abolish whole-islet [Ca 2+ ] IC activity in simulations, similarly to what was noted experimentally, but as mentioned before, only close to the threshold glucose stimulation ( 148 ). Later studies incorporating in-depth numerical analyses alleviated these findings a bit by showing that removing the metabolically most active and heavily connected cells or cells with the highest intrinsic frequencies does not diminish whole-islet activity ( 60 , 143 , 170 ). These results suggest that the whole-islet [Ca 2+ ] IC activity is probably not driven by a very small (<10%) subpopulation of extraordinary cells and that the islets are robust to loss of small groups of cells, even if they have special attributes, as would be expected for evolutionary robust assemblies of intrinsic oscillators ( 60 , 213 ).…”