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

Spatial distribution of heterogeneity as a modulator of collective dynamics in pancreatic beta-cell networks and beyond

“…We used two prototypical models of cellular excitability where a small population was highly excitable, whilst a larger population was less excitable. This scenario has recently been hypothesised to be relevant in beta cell networks, in particular in the description of ‘hubs’, populations displaying high functional connectivity ( Johnston et al, 2016 ), ‘wave-initiators’ (also known as ‘leaders’) ( Šterk et al, 2023 ), and ‘first-responders’ ( Kravets et al, 2022 ). As the global drive to the network was increased, activity across the network transitioned from a globally inactive state to one in which subsets of nodes became active and synchronised their activity.…”

“…In turn, the coordination of electrical activity is facilitated by local cell-cell communication through the gap junctional network ( Ravier et al, 2005 ). Recently, many studies have demonstrated the existence of β -cell heterogeneity and its importance in determining network dynamics ( Benninger et al, 2014 ; Benninger and Kravets, 2021 ; Johnston et al, 2016 ; Kravets et al, 2022 ; Nasteska et al, 2021 ; Salem et al, 2019 ; Šterk et al, 2023 ; Stožer et al, 2013 ; Westacott et al, 2017 ). Thus, a key question in this work has been to study the potential impact of the cytoarchitecture (e.g., spatial layout of heterogeneity) in modulating these dynamics.…”

“…The existence of these populations has been heavily implicated as a feature of healthy pancreatic islets, as has their critical roles in driving the collective dynamics required for GSIS. However, defining these subpopulations is complex because they likely arise as an emergent property of the network, relying on an interplay of both cell-intrinsic properties (i.e., excitability and metabolism) and network properties (i.e., coupling strength and non-uniformity of heterogeneity) ( Benninger et al, 2014 ; Kravets et al, 2022 ; Salem et al, 2019 ; Šterk et al, 2023 ; Westacott et al, 2017 ). For example, it appears that both first-responder cells ( Kravets et al, 2022 ) and wave-initiator cells ( Šterk et al, 2023 ) may have weaker local connectivity, a property that would isolate them from the hyperpolarising influence of less-excitable cells and could improve network responsiveness.…”

“…This type of connectivity scheme is commonly employed in β -cell network modelling studies ( Benninger et al, 2014 ; Dwulet et al, 2019 , 2021 ; Westacott et al, 2017 ), as it qualitatively captures the network architecture. In reality, pancreatic islet architecture is more complex in terms of islet shape, cell shape, and the layout of cells in the tissue ( Stožer et al, 2013 ; Šterk et al, 2023 ); all of which could be considered as additional sources of heterogeneity. Moreover, there may be heterogeneity in the number of connections that β -cells form amongst each other ( Cabrera et al, 2006 ).…”

“…In pancreatic islets, heterogeneity has increasingly been acknowledged as crucial for healthy glucose metabolism ( Nasteska et al, 2021 ), and classification of beta-cell populations in particular is an area of active investigation. Heterogeneity in cell-intrinsic properties (i.e., excitability, metabolic activity, and genetic profiles), network properties, and functional properties have all been demonstrated ( Johnston et al, 2016 ; Kravets et al, 2022 ; Nasteska et al, 2021 ; Šterk et al, 2023 ; Westacott et al, 2017 ).…”