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

ABSTRACT: Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic beta cell Pyroptosis upon Viral Infection

PROVIDER: PRJNA1040752 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26837008.fastq.gz	Fastqsanger.gz
	SRR26837009.fastq.gz	Fastqsanger.gz
	SRR26837010.fastq.gz	Fastqsanger.gz
	SRR26837011.fastq.gz	Fastqsanger.gz
	SRR26836512_1.fastq.gz	Fastqsanger.gz

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Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic beta cell Pyroptosis upon Viral Infection [bulkRNAseq]

Project description:Immune cells play critical roles in causing host damage in various diseases, including infectious diseases. However, there is a paucity of human models to study immune-mediated host damage. Here, we systematically analyzed the changes in immune cell composition for COVID-19 pancreatic autopsy samples using the GeoMx spatial RNA and protein platform and found accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets upon SARS-CoV-2 or Coxsackievirus B4 (CVB4) infection identified the activation of proinflammatory macrophages and pyroptosis in β cells. To distinguish whether the virus or proinflammatory macrophages mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids, containing pancreatic endocrine cells, endothelial cells, and macrophages. Both pancreatic β cells and endothelial cells in VMI organoids demonstrated improved marker expression and function compared to separately cultured cells. Additionally, proinflammatory macrophages in VMI organoids were found to induce β cell pyroptosis. Further mechanistic studies identified TNFSF12-TNFRSF12A as a contributor to proinflammatory macrophage-mediated β cell pyroptosis. Together, this study established a hPSC-derived VMI organoid as a valuable tool for studying immune cell-mediated host damage and uncovered previous unknown mechanism of β cell damage in viral infection.

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Project description: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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Project description:This SuperSeries is composed of the SubSeries listed below.

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