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<p>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<sup>2+</sup> overload. Transcriptomic analysis reveals that metabolically-stressed beta&#xa0;cells follow paths to either de-differentiation or apoptosis. Beta&#xa0;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&#xa0;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.</p>

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Developmental beta-cell death orchestrates the islet’s inflammatory milieu by regulating immune system crosstalk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月6日

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  • Mohammad Nadeem Akhtar,
  • Alisa Hnatiuk,
  • Luis Delgadillo-Silva,
  • Shirin Geravandi,
  • Katrin Sameith,
  • Susanne Reinhardt,
  • Katja Bernhardt,
  • Sumeet Pal Singh,
  • Kathrin Maedler,
  • Lutz Brusch,
  • Nikolay Ninov

摘要

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.