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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk.
EMBO J. 44, 1131-1153 (2025)
Verlagsversion
Forschungsdaten
DOI
PMC
While pancreatic beta-cell proliferation has been extensively studied, the role of cell death during islet development remains incompletely understood. Using a genetic model of caspase inhibition in beta cells coupled with mathematical modeling, we here discover an onset of beta-cell death in juvenile zebrafish, which regulates beta-cell mass. Histologically, this beta-cell death is underestimated due to phagocytosis by resident macrophages. To investigate beta-cell apoptosis at the molecular level, we implement a conditional model of beta-cell death linked to Ca2+ overload. Transcriptomic analysis reveals that metabolically-stressed beta cells follow paths to either de-differentiation or apoptosis. Beta cells destined to die activate inflammatory and immuno-regulatory pathways, suggesting that cell death regulates the crosstalk with immune cells. Consistently, inhibiting beta-cell death during development reduces pro-inflammatory resident macrophages and expands T-regulatory cells, the deficiency of which causes premature activation of NF-kB signaling in beta cells. Thus, developmental cell death not only shapes beta-cell mass but it also influences the islet's inflammatory milieu by shifting the immune-cell population towards pro-inflammatory.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Dedifferentiationp ; Excitotoxicity ; Macrophage ; T Regulatory Cell ; Type 1 Diabetes; Apoptosis; Activation; Mechanisms; Expression; Pancreas; Rat; Initiation; Lineage; Cd28
ISSN (print) / ISBN
0261-4189
e-ISSN
1460-2075
Zeitschrift
EMBO Journal, The
Quellenangaben
Band: 44,
Heft: 4,
Seiten: 1131-1153
Verlag
Wiley
Verlagsort
Heidelberg, Germany
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Pancreatic Islet Research (IPI)
Förderungen
DFG Research Grant
Network for Pancreatic Organ donors with Diabetes
Leona M. & Harry B. Helmsley Charitable Trust
Organ Procurement Organizations (OPO)
BMBF
DFG Research Grants
DFG- International Research Training Group
Bundesministerium fr Bildung und Forschung (BMBF)
Network for Pancreatic Organ donors with Diabetes
Leona M. & Harry B. Helmsley Charitable Trust
Organ Procurement Organizations (OPO)
BMBF
DFG Research Grants
DFG- International Research Training Group
Bundesministerium fr Bildung und Forschung (BMBF)