TY - JOUR
T1 - Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo
AU - Salem, Victoria
AU - Delgadillo Silva, Luis
AU - Suba, Kinga
AU - Georgiades, Eleni
AU - Mousavy Gharavy, S. Neda
AU - Akhtar, Nadeem
AU - Martin-Alonso, Aldara
AU - Gaboriau, David C. A.
AU - Rothery, Stephen M.
AU - Stylianides, Theodoros
AU - Carrat, Gaelle
AU - Pullen, Timothy J.
AU - Pal Singh, Sumeet
AU - Hodson, David
AU - Leclerc, Isabelle
AU - Shapiro, A. M. James
AU - Marchetti, Piero
AU - Briant, Linford J. B.
AU - Distaso, Walter
AU - Ninov, Nikolay
AU - Rutter, Guy A.
PY - 2019/6/14
Y1 - 2019/6/14
N2 - 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.
AB - 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.
KW - GCaMP6
KW - Granger causality
KW - ca2+ dynamics
KW - cluster analysis
KW - connectivity
KW - functional imaging
KW - in vivo
KW - pancreatic islet
KW - photo-ablation
KW - transcriptomics
KW - zebrafish
KW - β cell
UR - http://www.scopus.com/inward/record.url?scp=85068517633&partnerID=8YFLogxK
U2 - 10.1038/s42255-019-0075-2
DO - 10.1038/s42255-019-0075-2
M3 - Article
SN - 0028-0836
VL - 1
SP - 615
EP - 629
JO - Nature
JF - Nature
IS - 6
ER -