研究免疫介导的宿主损伤的人体模型很少。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，揭示了促炎巨噬细胞的积累。对暴露于严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 或柯萨奇病毒 B4 (CVB4) 病毒的人类胰岛进行单细胞 RNA 测序 (scRNA-seq) 分析，发现促炎巨噬细胞和 β 细胞焦亡被激活。为了区分病毒和促炎巨噬细胞介导的 β 细胞焦亡，我们开发了人多能干细胞 (hPSC) 来源的血管化巨噬细胞胰岛 (VMI) 类器官。与单独培养的细胞相比，VMI 类器官在 β 细胞和内皮细胞中表现出增强的标记表达和功能。值得注意的是，VMI 类器官内的促炎巨噬细胞诱导 β 细胞焦亡。机制研究强调 TNFSF12-TNFRSF12A 参与促炎巨噬细胞介导的 β 细胞焦亡。这项研究建立了 hPSC 衍生的 VMI 类器官作为研究免疫细胞介导的宿主损伤的重要工具，并揭示了病毒暴露期间 β 细胞损伤的机制。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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 sequencing (scRNA-seq) analysis of human islets exposed to severe acute respiratory syndrome coronavirus 2 (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 with 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 the mechanism of β cell damage during viral exposure.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.