Article Synopsis
- - The study investigates immune-mediated damage in the pancreas during COVID-19, revealing a buildup of harmful proinflammatory macrophages in human autopsy samples.
- - Researchers employed advanced techniques, including single-cell RNA sequencing and human pluripotent stem cell-derived organoids, to study how these macrophages trigger β cell pyroptosis in response to SARS-CoV-2 and coxsackievirus B4.
- - The findings identified a specific interaction (TNFSF12-TNFRSF12A) that mediates this damage, positioning the derived vascularized macrophage-islet organoids as crucial tools for further research on immune responses in viral infections.
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Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11546835 | PMC |
| http://dx.doi.org/10.1016/j.stem.2024.08.007 | DOI Listing |
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