| Title | Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Yang, L, Han, Y, Zhang, T, Dong, X, Ge, J, Roy, A, Zhu, J, Lu, T, J Vandana, J, de Silva, N, Robertson, CC, Xiang, JZ, Pan, C, Sun, Y, Que, J, Evans, T, Liu, C, Wang, W, Naji, A, Parker, SCJ, Schwartz, RE, Chen, S |
| Journal | Cell Stem Cell |
| Date Published | 2024 Aug 30 |
| ISSN | 1875-9777 |
| 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. |
| DOI | 10.1016/j.stem.2024.08.007 |
| Alternate Journal | Cell Stem Cell |
| PubMed ID | 39232561 |