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Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning

dc.rights.licenseopenen_US
dc.contributor.authorHONG, J.
dc.contributor.authorARNESON, D.
dc.contributor.authorUMAR, S.
dc.contributor.authorRUFFENACH, G.
dc.contributor.authorCUNNINGHAM, C. M.
dc.contributor.authorAHN, I. S.
dc.contributor.authorDIAMANTE, G.
dc.contributor.authorBHETRARATANA, M.
dc.contributor.authorPARK, J. F.
dc.contributor.authorSAID, E.
dc.contributor.authorHUYNH, C.
dc.contributor.authorLE, T.
dc.contributor.authorMEDZIKOVIC, L.
dc.contributor.authorHUMBERT, M.
dc.contributor.authorSOUBRIER, F.
dc.contributor.authorMONTANI, D.
dc.contributor.authorGIRERD, B.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorCHANNICK, R.
dc.contributor.authorSAGGAR, R.
dc.contributor.authorEGHBALI, M.
dc.contributor.authorYANG, X.
dc.date.accessioned2021-03-23T09:17:24Z
dc.date.available2021-03-23T09:17:24Z
dc.date.issued2020-10-06
dc.identifier.issn1073-449xen_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/26785
dc.description.abstractEnRATIONALE: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation. OBJECTIVES: We aim to determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates. METHODS: Single-cell RNA-seq was performed on the lungs of monocrotaline, Sugen-hypoxia, and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map. MEASUREMENTS AND MAIN RESULTS: Distinct changes in genes and pathways in numerous cell types were identified in Sugen-hypoxia and monocrotaline lungs. Widespread upregulation of NF-κB signaling and downregulation of interferon signaling was observed across cell types. Sugen-hypoxia non-classical monocytes and monocrotaline conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in Sugen-hypoxia non-classical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics. RESEARCH: idre.ucla.edu/PVDSingleCell/). CONCLUSIONS: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.
dc.language.isoENen_US
dc.title.enSingle-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning
dc.title.alternativeAm J Respir Crit Care Meden_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1164/rccm.202006-2169OCen_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed33021809en_US
bordeaux.journalAmerican Journal of Respiratory and Critical Care Medicineen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.exportfalse
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