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 Wang, Ali Naji, Stephen C.J. Parker, Robert E. Schwartz, Shuibing Chen
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.