Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection

IF 19.8 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2024-09-03 DOI:10.1016/j.stem.2024.08.007

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, 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 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.

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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 细胞脓毒症

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，揭示了促炎性巨噬细胞的积累。对暴露于严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）或柯萨奇病毒 B4（CVB4）病毒的人类胰岛进行的单细胞 RNA 测序（scRNA-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 器官内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 细胞坏死。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。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.