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

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

doi:10.1016/j.stem.2024.08.007

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

Cell Stem Cell. 2024 Nov 7;31(11):1612-1629.e8. doi: 10.1016/j.stem.2024.08.007. Epub 2024 Sep 3.

Authors

Liuliu Yang¹, Yuling Han², Tuo Zhang³, Xue Dong⁴, Jian Ge⁵, Aadita Roy⁴, Jiajun Zhu⁶, Tiankun Lu⁶, J Jeya Vandana⁶, Neranjan de Silva⁶, Catherine C Robertson⁷, Jenny Z Xiang³, Chendong Pan³, Yanjie Sun³, Jianwen Que⁵, Todd Evans⁶, Chengyang Liu⁸, Wei Wang⁸, Ali Naji⁸, Stephen C J Parker⁹, Robert E Schwartz¹⁰, Shuibing Chen¹¹

Affiliations

¹ 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. Electronic address: yangliuliu@ihcams.ac.cn.
² 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.
³ Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
⁴ Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
⁵ Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁶ 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.
⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
⁹ 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.
¹⁰ 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. Electronic address: res2025@med.cornell.edu.
¹¹ 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. Electronic address: shc2034@med.cornell.edu.

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.

Keywords: SARS-CoV-2; coxsackievirus B4; diabetes; endothelial cells; human pluripotent stem cells; organoids; pancreatic endocrine cells; proinflammatory macrophages; pyroptosis.

MeSH terms

COVID-19 / immunology
COVID-19 / pathology
COVID-19 / virology
Humans
Insulin-Secreting Cells* / immunology
Insulin-Secreting Cells* / pathology
Insulin-Secreting Cells* / virology
Macrophages* / immunology
Macrophages* / metabolism
Macrophages* / virology
Organoids* / immunology
Organoids* / pathology
Organoids* / virology
Pluripotent Stem Cells / metabolism
Pyroptosis*
SARS-CoV-2 / immunology

Abstract

MeSH terms

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