Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection

bioRxiv - Developmental Biology Pub Date : 2024-08-06 DOI:10.1101/2024.08.05.606734

Liuliu Yang, Yuling Han, Tuo Zhang, Xue Dong, Jian Ge, Aadita Roy, Jiajun Zhu, Tiankun Lu, J. Jeya Vandana, Neranjan de Silva, Catherine C. Robertson, Jenny Z Xiang, Chendong Pan, Yanjie Sun, Jianwen Que, Todd Evans, Chengyang Liu, Wei Wang, Ali Naji, Stephen C.J. Parker, Robert E. Schwartz, Shuibing Chen

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Abstract

There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated β cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of β cell damage during viral exposure.

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用人血管化巨噬细胞-胰岛器官组织模拟病毒感染时免疫介导的胰腺 β 细胞猝灭现象

研究免疫介导的宿主损伤的人体模型非常缺乏。在这里，我们利用 GeoMx 空间多组学平台分析了 COVID-19 胰腺尸检样本中免疫细胞的变化，发现了促炎性巨噬细胞的积累。对暴露于SARS-CoV-2或柯萨奇病毒B4（CVB4）病毒的人胰岛进行的单细胞RNA-seq分析发现了促炎性巨噬细胞的激活和β细胞的热解。为了区分病毒和促炎巨噬细胞介导的β细胞脓毒症，我们开发了人多能干细胞（hPSC）衍生的血管化巨噬细胞-胰岛（VMI）器官组织。与单独培养的细胞相比，VMI器官组织在β细胞和内皮细胞中的标志物表达和功能都有所增强。值得注意的是，VMI器官组织中的促炎巨噬细胞诱导了β细胞的热解。机理研究强调 TNFSF12-TNFRSF12A 参与了促炎巨噬细胞介导的 β 细胞热解过程。这项研究确立了 hPSC 衍生的 VMI 器官组织是研究免疫细胞介导的宿主损伤的重要工具，并揭示了病毒暴露过程中 β 细胞损伤的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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bioRxiv - Developmental Biology

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