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 Xiang; Chendong Pan; Yanjie Sun; Jianwen Que; Todd Evans; Chengyang Liu; Wei J. Wang; Ali Naji; Stephen C.J. Parker; Robert E. Schwartz; Shuibing Chen

doi:10.1016/j.stem.2024.08.007

Developmental BiologyCell stem cellSep 2, 2024

Peer-reviewed journal article

Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection

Liuliu Yang iD, Yuling Han iD, Tuo Zhang iD, Xue Dong iD, Jian Ge iD, Aadita Roy, Jiajun Zhu iD, Tiankun Lu iD, J. Jeya Vandana iD, Neranjan de Silva, Catherine C. Robertson iD, Jenny Xiang iD, Chendong Pan iD, Yanjie Sun, Jianwen Que iD, Todd Evans iD, Chengyang Liu iD, Wei J. Wang iD, Ali Naji iD, Stephen C.J. Parker iD, Robert E. Schwartz iD, Shuibing Chen iD

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-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and {beta} cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated {beta} 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 {beta} cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced {beta} cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated {beta} cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of {beta} cell damage during viral exposure.

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