Abstract
Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected 'hub' cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.
Highlights
As we found that glucose injection in zebrafish larvae at relatively low acquisition speed (0.1Hz) triggers a synchronous Ca2+ response across the islet, we decided to explore in more detail whether this apparent synchronous response was initiated faster by some of the islet cells, or if all cells activated simultaneously
We tested the function of these leader β-cells by laser ablation and we found that their ablation led to a significant reduction in the total islet GCaMP response to a glucose stimulus
We explored the Ca2+ dynamics of the β-cell in their native unaltered microenvironment
Summary
Guy Rutter Faculty of Medicine, Department of Metabolism, Digestion and Reproduction Department of Medicine, Imperial College London, London, UK. Anmerkung: Die Eintragung der Gutachter und Tag der mündlichen Prüfung (Verteidigung) erfolgt nach Festlegung von Seiten der Medizinischen Fakultät Carl Gustav Carus der Technischen Universität Dresden. Die oben genannten Eintragungen werden durch die Doktoranden nach der Verteidigung zwecks Übergabe der fünf Pflichtexemplare an die Zweigbibliothek Medizin in gedruckter Form oder handschriftlich vorgenommen
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