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Akhtar, M.N. ; Hnatiuk, A. ; Delgadillo-Silva, L.F.* ; Geravandi, S.* ; Sameith, K.* ; Reinhardt, S.* ; Bernhardt, K.* ; Singh, S.P.* ; Maedler, K.* ; Brusch, L.* ; Ninov, N.

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
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 44, Heft: 4, Seiten: 1131-1153 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)
POF Topic(s) 90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502600-010
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)
DOI 10.1038/s44318-024-00332-w
WOS ID 001390295200001
Scopus ID 85214209472
PubMed ID 39762647
Erfassungsdatum 2025-03-21
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