Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection
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.
Authors
- Todd Evans (ORCID: https://orcid.org/0000-0002-7148-9849)
- Chendong Pan (ORCID: https://orcid.org/0000-0003-3058-7247)
- J. Jeya Vandana (ORCID: https://orcid.org/0000-0002-1026-569X)
- Shuibing Chen (ORCID: https://orcid.org/0000-0002-6294-5187)
- Jiajun Zhu (ORCID: https://orcid.org/0000-0003-2357-267X)
- Catherine C. Robertson (ORCID: https://orcid.org/0000-0002-1120-1786)
- Jenny Xiang (ORCID: https://orcid.org/0000-0003-0484-2769)
- Yanjie Sun
- Robert E. Schwartz (ORCID: https://orcid.org/0000-0002-5417-5995)
- Stephen C.J. Parker (ORCID: https://orcid.org/0000-0001-8122-0117)
- Tiankun Lu (ORCID: https://orcid.org/0000-0002-8483-2087)
- Jianwen Que (ORCID: https://orcid.org/0000-0002-6540-6701)
- Liuliu Yang (ORCID: https://orcid.org/0000-0003-0121-4214)
- Neranjan de Silva
- Ali Naji (ORCID: https://orcid.org/0000-0002-6926-3306)
- Tuo Zhang (ORCID: https://orcid.org/0000-0001-5396-918X)
- Chengyang Liu (ORCID: https://orcid.org/0000-0002-5802-1547)
- Xue Dong (ORCID: https://orcid.org/0000-0001-5243-6453)
- Yuling Han (ORCID: https://orcid.org/0000-0002-6805-4094)
- Jian Ge
- Aadita Roy
- Wei J. Wang (ORCID: https://orcid.org/0000-0002-4848-7394)
Institutions
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Cornell University (US)
- University of Michigan (US)
- Columbia University Irving Medical Center (US)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Genomic Health (United States) (US)
- Institute of Zoology (CN)
- Weill Cornell Medicine (US)
- State Key Laboratory of Stem Cell and Reproductive Biology
- University of Pennsylvania (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1016/j.stem.2024.08.007
- Citations
- 33
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 18.90
Funders
- Bill and Melinda Gates Foundation
- University of Pennsylvania
- National Institutes of Health
- Weill Cornell Medical College
- National Institute of Diabetes and Digestive and Kidney Diseases