Akhtar Mohammad Nadeem, Hnatiuk Alisa, Delgadillo-Silva Luis, Geravandi Shirin, Sameith Katrin, Reinhardt Susanne, Bernhardt Katja, Singh Sumeet Pal, Maedler Kathrin, Brusch Lutz, Ninov Nikolay
Centre for Regenerative Therapies TU Dresden, Dresden, 01307, Germany.
Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus of TU Dresden, German Center for Diabetes Research (DZD e.V.), Dresden, 01307, Germany.
EMBO J. 2025 Feb;44(4):1131-1153. doi: 10.1038/s44318-024-00332-w. Epub 2025 Jan 6.
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 Ca 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.
虽然胰腺β细胞增殖已得到广泛研究，但胰岛发育过程中细胞死亡的作用仍未完全了解。我们利用β细胞中半胱天冬酶抑制的遗传模型并结合数学建模，在此发现幼年斑马鱼中β细胞死亡的起始，其可调节β细胞质量。从组织学上看，由于驻留巨噬细胞的吞噬作用，这种β细胞死亡被低估。为了在分子水平上研究β细胞凋亡，我们实施了一种与钙超载相关的β细胞死亡条件模型。转录组分析表明，代谢应激的β细胞会走向去分化或凋亡。注定死亡的β细胞会激活炎症和免疫调节途径，这表明细胞死亡调节与免疫细胞的相互作用。一致地，在发育过程中抑制β细胞死亡会减少促炎驻留巨噬细胞并增加调节性T细胞，而调节性T细胞的缺乏会导致β细胞中NF-κB信号过早激活。因此，发育性细胞死亡不仅塑造了β细胞质量，还通过将免疫细胞群体转向促炎状态来影响胰岛的炎症环境。
