Delineating mouse β-cell identity during lifetime and in diabetes with a single cell atlas

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(9), P. 1615 - 1637

Published: Sept. 11, 2023

Although multiple pancreatic islet single-cell RNA-sequencing (scRNA-seq) datasets have been generated, a consensus on cell states in development, homeostasis and diabetes as well the value of preclinical animal models is missing. Here, we present an scRNA-seq cross-condition mouse atlas (MIA), curated resource for interactive exploration computational querying. We integrate over 300,000 cells from nine consisting 56 samples, varying age, sex models, including autoimmune type 1 model (NOD), glucotoxicity/lipotoxicity 2 (db/db) chemical streptozotocin β-cell ablation model. The landscape MIA reveals new during disease progression cross-publication differences between previously suggested marker genes. show that β-cells transcriptionally correlate with those human db/db but are less similar to NOD β-cells. also report pathways shared immature, aged models. enables comprehensive analysis responses different stressors, providing roadmap understanding plasticity, compensation demise.

Language: Английский

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Ca2+ Oscillations, Waves, and Networks in Islets From Human Donors With and Without Type 2 Diabetes

Diabetes, Journal Year: 2022, Volume and Issue: 71(12), P. 2584 - 2596

Published: Sept. 6, 2022

Pancreatic islets are highly interconnected structures that produce pulses of insulin and other hormones, maintaining normal homeostasis glucose nutrients. Normal stimulus-secretion intercellular coupling essential to regulated secretory responses, these hallmarks known be altered in diabetes. In the current study, we used calcium imaging isolated human assess their collective behavior. The activity occurred form oscillations, was synchronized across different regions through waves, dependent: higher enhanced activity, elicited a greater proportion global led denser less fragmented functional networks. Hub were identified stimulatory conditions, they characterized by long active times. Moreover, waves found initiated subregions roles initiators hubs did not overlap. type 2 diabetes, dependence retained, but reduced locally restricted more segregated networks detected compared with control islets. Interestingly, hub seemed suffer most losing disproportionately large fraction connections. These changes affected from donors diabetes heterogeneous manner.

Language: Английский

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

Biophysical Journal, Journal Year: 2023, Volume and Issue: 122(5), P. 784 - 801

Published: Feb. 2, 2023

Islets of Langerhans operate as multicellular networks in which several hundred β cells work synchrony to produce secretory pulses insulin, a hormone crucial for controlling metabolic homeostasis. Their collective rhythmic activity is facilitated by gap junctional coupling and affected their functional heterogeneity, but the details this robust coordinated behavior are still not fully understood. Recent advances imaging optogenetic photopharmacological strategies, well network science, have led discovery specialized cell subpopulations that were suggested critically determine dynamics islets. In particular hubs, i.e., with many connections, believed significantly enhance communication capacities intercellular facilitate an efficient spreading Ca

Language: Английский

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Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis

PLoS Computational Biology, Journal Year: 2024, Volume and Issue: 20(5), P. e1012130 - e1012130

Published: May 13, 2024

Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect metabolic homeostasis. Despite inherent heterogeneity and multimodal activity individual cells, intercellular coupling acts as homogenizing force, enabling coordinated responses through propagation waves. Disruptions in this coordination are implicated irregular hallmark diabetes. Recently, innovative approaches, such integrating multicellular calcium imaging with network analysis, have emerged for quantitative assessment cellular islets. However, different groups use distinct experimental preparations, microscopic techniques, apply methods to process measured signals various derive functional connectivity patterns. This makes comparisons between findings their integration into bigger picture difficult has led disputes interpretations. To address these issues, we present here systematic analysis how approaches influence representation islet activity. Our show that choice used construct networks is not crucial, although care needed when combining data from Conversely, conclusions drawn can be heavily affected by pre-processing time series, type oscillatory component signals, preparation. tutorial-like investigation aims resolve interpretational reconcile conflicting views, advance implications, encourage researchers adopt analysis. As conclude, outline challenges future research, emphasizing broader applicability our other tissues exhibiting complex dynamics.

Language: Английский

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Optogenetic β cell interrogation in vivo reveals a functional hierarchy directing the Ca ²⁺ response to glucose supported by vitamin B6

Science Advances, Journal Year: 2024, Volume and Issue: 10(26)

Published: June 26, 2024

Coordination of cellular activity through Ca

Language: Английский

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Beta-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Nov. 29, 2023

Diabetes is caused by the inability of electrically coupled, functionally heterogeneous β-cells within pancreatic islet to provide adequate insulin secretion. Functional networks have been used represent synchronized oscillatory [Ca2+] dynamics and study β-cell subpopulations, which play an important role in driving function. The mechanism highly subpopulations drive function unclear. We experimental computational techniques investigate relationship between functional networks, structural (gap junction) intrinsic slow fast oscillating islets. Highly network were differentiated dynamics, including metabolic activity KATP channel conductance, more than coupling. Consistent with this, predictive high synchronization as compared levels Finally, dysfunction gap junctions, can occur diabetes, decreases efficiency clustering network. These results indicate that rather structure connections but junctions are still essential for overall efficiency. findings deepen our interpretation formation dynamic tissues such islet.

Language: Английский

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Determinants of collective failure in excitable networks

Chaos An Interdisciplinary Journal of Nonlinear Science, Journal Year: 2023, Volume and Issue: 33(4)

Published: April 1, 2023

We study collective failures in biologically realistic networks that consist of coupled excitable units. The have broad-scale degree distribution, high modularity, and small-world properties, while the dynamics is determined by paradigmatic FitzHugh–Nagumo model. consider different coupling strengths, bifurcation distances, various aging scenarios as potential culprits failure. find for intermediate network remains globally active longest if high-degree nodes are first targets inactivation. This agrees well with previously published results, which showed oscillatory can be highly fragile to targeted inactivation low-degree nodes, especially under weak coupling. However, we also show most efficient strategy enact failure does not only non-monotonically depend on strength, but it depends distance from point behavior individual Altogether, provide a comprehensive account determinants networks, hope this will prove useful better understanding breakdowns systems subject such dynamics.

Language: Английский

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Both electrical and metabolic coupling shape the collective multimodal activity and functional connectivity patterns in beta cell collectives: A computational model perspective

Physical review. E, Journal Year: 2023, Volume and Issue: 108(5)

Published: Nov. 22, 2023

Pancreatic beta cells are coupled excitable oscillators that synchronize their activity via different communication pathways. Their oscillatory manifests itself on multiple timescales and consists of bursting electrical activity, subsequent oscillations in the intracellular ${\mathrm{Ca}}^{2+}$, as well metabolism exocytosis. The coordination intricate multicellular level plays a key role regulation physiological pulsatile insulin secretion is incompletely understood. In this paper, we investigate theoretically principles give rise to synchronized cell populations by building up phenomenological model incorporates basic features dynamics. Specifically, composed slow fast units reflect metabolic processes respectively. Using realistic description intercellular interactions, study how combination coupling generates collective rhythmicity shapes functional networks. It turns out while solely can responses, addition interactions further enhances coordination, spatial range increases number connections networks, ensures better consistency with experimental findings. Moreover, our computational results provide additional insights into relationship between heterogeneity, profiles, connectivity, supplementing thereby recent endocrine

Language: Английский

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Glucokinase activity controls peripherally located subpopulations of β-cells that lead islet Ca2+ oscillations

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 12, 2025

Oscillations in insulin secretion, driven by islet Ca 2+ waves, are crucial for glycemic control. Prior studies, performed with single-plane imaging, suggest that subpopulations of electrically coupled β-cells have privileged roles leading and coordinating the propagation waves. Here, we used three-dimensional (3D) light-sheet imaging to analyze location activity single within entire at >2 Hz. In contrast 3D network analysis indicates most highly synchronized located center, remain regionally but not cellularly stable between oscillations. This subpopulation, which includes ‘hub cells’, is insensitive changes fuel metabolism induced glucokinase pyruvate kinase activation. β-Cells initiate wave (leaders) periphery, strikingly, change their identity over time via rotations axis. Glucokinase activation, increased oscillation period, reinforced leader cells stabilized Pyruvate despite increasing frequency, had no effect on cells, indicating origin patterned input. These findings emphasize stochastic nature β-cell control oscillations identify a role spatially patterning ‘leader’ β-cells.

Language: Английский

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Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 16, 2024

Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis energy-rich nutrients. While glucose serves as a primary regulator this process, incretins augment function, partly by enhancing cytosolic [Ca 2+ ] dynamics. However, the details how precisely they affect recruitment during activation, their active time, and functional connectivity plateau activity, influence deactivation remain to be described. Performing multicellular Ca imaging in acute mouse pancreas tissue slices enabled us systematically assess effects GLP-1 receptor agonist exendin-4 (Ex-4) simultaneously many coupled cells with high resolution. In otherwise substimulatory glucose, Ex-4 was able recruit approximately quarter into an state. Costimulation stimulatory shortened activation delays accelerated More specifically, time increased faster, required reach half-maximal effectively halved presence Ex-4. Moreover, regularity IC oscillations increased, especially first part response. contrast, subsequent addition already did not significantly enhance activity. Network analyses further confirmed activity Ex-4, hub roles remaining rather stable both experiments Interestingly, demonstrated biphasic effect on deactivation, slightly prolonging at physiological concentrations shortening supraphysiological concentrations. sum, costimulation increases indicating that may, important extent, explained enhanced signals. During previous incretin stimulation does critically prolong cellular which corroborates low risk hypoglycemia.

Language: Английский

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