2. Academic Validation
  3. Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection

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

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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