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

  • bioRxiv. 2024 Aug 6:2024.08.05.606734. doi: 10.1101/2024.08.05.606734.
Liuliu Yang  1  2  3  4 ,  Yuling Han  1  2  5  6  7 ,  Tuo Zhang  8 ,  Xue Dong  1 ,  Jian Ge  9 ,  Aadita Roy  1 ,  Jiajun Zhu  1  2 ,  Tiankun Lu  1  2 ,  J Jeya Vandana  1  2 ,  Neranjan de Silva  1  2 ,  Catherine C Robertson  10 ,  Jenny Z Xiang  8 ,  Chendong Pan  8 ,  Yanjie Sun  8 ,  Jianwen Que  9 ,  Todd Evans  1  2 ,  Chengyang Liu  11 ,  Wei Wang  11 ,  Ali Naji  11 ,  Stephen C J Parker  10  12  13 ,  Robert E Schwartz  14  15 ,  Shuibing Chen  1  2
Affiliations
  • 1. Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.
  • 2. Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.
  • 3. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Disease, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
  • 4. Tianjin Institute of Health Science, Tianjin 301600, China.
  • 5. Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 6. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
  • 7. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
  • 8. Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
  • 9. Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 10. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • 11. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
  • 12. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
  • 13. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • 14. Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.
  • 15. Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA. New York 10021, USA.
PMID: 39149298 DOI: 10.1101/2024.08.05.606734
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 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 to 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 mechanism of β cell damage during viral exposure.

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