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Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk.
EMBO J. 44, 1131-1153 (2025)
Publ. Version/Full Text
Research data
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
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
Journal
EMBO Journal, The
Quellenangaben
Volume: 44,
Issue: 4,
Pages: 1131-1153
Publisher
Wiley
Publishing Place
Heidelberg, Germany
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Pancreatic Islet Research (IPI)
Grants
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)