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

Yang, L.; Han, Y.; Zhang, T.; Dong, X.; Ge, J.; Roy, A.; Zhu, J.; Lu, T.; Vandana, J. J.; de Silva, N.; Robertson, C. C.; Xiang, J. Z.; Pan, C.; Sun, Y.; Que, J.; Evans, T.; Liu, C.; Wang, W.; Naji, A.; Parker, S. C. J.; Schwartz, R. E.; Chen, S.

doi:10.1101/2024.08.05.606734

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bioRxiv · 10.1101/2024.08.05.606734

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

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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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Yang, L., Han, Y., Zhang, T., Dong, X., Ge, J., Roy, A., Zhu, J., Lu, T., Vandana, J. J., de Silva, N., Robertson, C. C., Xiang, J. Z., Pan, C., Sun, Y., Que, J., Evans, T., Liu, C., Wang, W., Naji, A., Parker, S. C. J., Schwartz, R. E., Chen, S.. 2024-08-06. Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection. https://doi.org/10.1101/2024.08.05.606734

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