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

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Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-09-03 , DOI: 10.1016/j.stem.2024.08.007
Liuliu Yang ₁ , Yuling Han ₂ , Tuo Zhang ₃ , Xue Dong ₄ , Jian Ge ₅ , Aadita Roy ₄ , Jiajun Zhu ₆ , Tiankun Lu ₆ , J Jeya Vandana ₆ , Neranjan de Silva ₆ , Catherine C Robertson ₇ , Jenny Z Xiang ₃ , Chendong Pan ₃ , Yanjie Sun ₃ , Jianwen Que ₅ , Todd Evans ₆ , Chengyang Liu ₈ , Wei Wang ₈ , Ali Naji ₈ , Stephen C J Parker ₉ , Robert E Schwartz ₁₀ , Shuibing Chen ₆

Affiliation

Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Disease, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institute of Health Science, Tianjin 301600, China.
Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.

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.

中文翻译：

人血管化巨噬细胞-胰岛类器官，用于模拟病毒感染后免疫介导的胰腺β细胞焦亡

缺乏研究免疫介导的宿主损伤的人体模型。在这里，我们利用 GeoMx 空间多组学平台分析 COVID-19 胰腺尸检样本中的免疫细胞变化，揭示了促炎巨噬细胞的积累。对暴露于严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2）或柯萨奇病毒 B4 （CVB4）病毒的人胰岛进行单细胞 RNA 测序（scRNA-seq）分析，确定了促炎巨噬细胞的激活和β细胞焦亡。为了区分病毒与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）衍生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志物表达和功能。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。机制研究强调了 TNFSF12-TNFRSF12A 参与促炎巨噬细胞介导的 β 细胞焦亡。本研究确定了 hPSC 衍生的 VMI 类器官作为研究免疫细胞介导的宿主损伤的宝贵工具，并揭示了病毒暴露过程中β细胞损伤的机制。

更新日期：2024-09-03

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