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HPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection.

ABSTRACT: hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection.

PROVIDER: PRJNA672671 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12914556_1.fastq.gz	Fastqsanger.gz
	SRR12914556_2.fastq.gz	Fastqsanger.gz
	SRR12914557_1.fastq.gz	Fastqsanger.gz
	SRR12914557_2.fastq.gz	Fastqsanger.gz
	SRR12914558_1.fastq.gz	Fastqsanger.gz

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hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection [scRNA-seq]

Project description:SARS-CoV-2, the virus causing recently pandemic, primarily infects the respiratory tract. There is an urgent need to develop platforms using disease relevant human cells to dissect the molecular mechanism regulating SARS-CoV-2 infection and perform drug screen. Here, we derived airway organoids from human pluripotent stem cells (hPSC-AO). The hPSC-AOs, particularly ciliated cells, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-AOs, we performed a high content screen and identified GW6471, which blocks SARS-CoV-2 infection. RNA-seq analysis suggested that GW6471 blocking SARS-CoV-2 infection by inhibiting HIF1α, which is further validated by chemotin, another HIF1α inhibitor. Furthermore, metabolic profiling identified that the downregulation of glycolysis upon GW6471 treatment, which is further validated by RNA-seq. Finally, xanthohumol, a prenylated flavonoid suppressing fatty acid and cholesterol biosynthesis, blocks SARS-CoV-2 infection. Together, we applied the high content screen, RNA-seq and metabolic profiling to define the key role of HIF1α-glycolysis axis in SARS-CoV-2 infection, which provides a target pathway for anti-viral drug development.

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hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection [scRNA-seq]

Project description:hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection [scRNA-seq]

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hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection [bulk RNA-seq]

Project description:hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection [bulk RNA-seq]

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An Airway Organoid-Based Screen Identifies a Role for the HIF1α-Glycolysis Axis in SARS-CoV-2 Infection

Project description:SARS-CoV-2 causes the COVID-19 pandemic. It is urgent to develop disease models to dissect mechanisms regulating SARS-CoV-2 infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA-seq analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting HIF1α, which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(Tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.

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hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection.

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Project description:First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.

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