Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning
| dc.rights.license | open | en_US |
| dc.contributor.author | HONG, J. | |
| dc.contributor.author | ARNESON, D. | |
| dc.contributor.author | UMAR, S. | |
| dc.contributor.author | RUFFENACH, G. | |
| dc.contributor.author | CUNNINGHAM, C. M. | |
| dc.contributor.author | AHN, I. S. | |
| dc.contributor.author | DIAMANTE, G. | |
| dc.contributor.author | BHETRARATANA, M. | |
| dc.contributor.author | PARK, J. F. | |
| dc.contributor.author | SAID, E. | |
| dc.contributor.author | HUYNH, C. | |
| dc.contributor.author | LE, T. | |
| dc.contributor.author | MEDZIKOVIC, L. | |
| dc.contributor.author | HUMBERT, M. | |
| dc.contributor.author | SOUBRIER, F. | |
| dc.contributor.author | MONTANI, D. | |
| dc.contributor.author | GIRERD, B. | |
| hal.structure.identifier | Bordeaux population health [BPH] | |
| dc.contributor.author | TREGOUET, David-Alexandre | |
| dc.contributor.author | CHANNICK, R. | |
| dc.contributor.author | SAGGAR, R. | |
| dc.contributor.author | EGHBALI, M. | |
| dc.contributor.author | YANG, X. | |
| dc.date.accessioned | 2021-03-23T09:17:24Z | |
| dc.date.available | 2021-03-23T09:17:24Z | |
| dc.date.issued | 2020-10-06 | |
| dc.identifier.issn | 1073-449x | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/26785 | |
| dc.description.abstractEn | RATIONALE: 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.iso | EN | en_US |
| dc.title.en | Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning | |
| dc.title.alternative | Am J Respir Crit Care Med | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1164/rccm.202006-2169OC | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Santé publique et épidémiologie | en_US |
| dc.identifier.pubmed | 33021809 | en_US |
| bordeaux.journal | American Journal of Respiratory and Critical Care Medicine | en_US |
| bordeaux.hal.laboratories | Bordeaux Population Health Research Center (BPH) - UMR 1219 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.team | VINTAGE | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| hal.export | false | |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=American%20Journal%20of%20Respiratory%20and%20Critical%20Care%20Medicine&rft.date=2020-10-06&rft.eissn=1073-449x&rft.issn=1073-449x&rft.au=HONG,%20J.&ARNESON,%20D.&UMAR,%20S.&RUFFENACH,%20G.&CUNNINGHAM,%20C.%20M.&rft.genre=article |
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