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Single-Cell RNA Sequencing and Quantitative Proteomics Analysis Elucidate Marker Genes and Molecular Mechanisms in Hypoplastic Left Heart Patients With Heart Failure

Authors
  • Ma, Li1, 2, 3
  • Zhou, Na2
  • Zou, Rongjun2
  • Shi, Wanting4
  • Luo, Yuanyuan3
  • Du, Na5
  • Zhong, Jing5
  • Zhao, Xiaodong3
  • Chen, Xinxin2
  • Xia, Huimin1, 3
  • Wu, Yueheng6, 7
  • 1 The First Affiliated Hospital of Jinan University, Guangzhou , (China)
  • 2 Heart Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou , (China)
  • 3 Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou , (China)
  • 4 Department of Paediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou , (China)
  • 5 Department of Surgical Nursing, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou , (China)
  • 6 Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangzhou , (China)
  • 7 Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou , (China)
Type
Published Article
Journal
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Publication Date
Feb 25, 2021
Volume
9
Identifiers
DOI: 10.3389/fcell.2021.617853
Source
Frontiers
Keywords
Disciplines
  • Cell and Developmental Biology
  • Original Research
License
Green

Abstract

Objective To probe markers and molecular mechanisms of the hypoplastic left heart (HLH) by single-cell RNA sequencing (scRNA-seq) and quantitative proteomics analysis. Methods Following data preprocessing, scRNA-seq data of pluripotent stem cell (iPSC)-derived cardiomyocytes from one HLH patient and one control were analyzed by the Seurat package in R. Cell clusters were characterized, which was followed by a pseudotime analysis. Markers in the pseudotime analysis were utilized for functional enrichment analysis. Quantitative proteomics analysis was based on peripheral blood samples from HLH patients without heart failure (HLH-NHF), HLH patients with heart failure (HLH-HF), and healthy controls. Hub genes were identified by the intersection of pseudotime markers and differentially expressed proteins (DE-proteins), which were validated in the GSE77798 dataset, RT-qPCR, and western blot. Results Cardiomyocytes derived from iPSCs were clustered into mesenchymal stem cells, myocardium, and fibroblast cells. Pseudotime analysis revealed their differentiation trajectory. Markers in the three pseudotime clusters were significantly associated with distinct biological processes and pathways. Finally, three hub genes (MMP2, B2M, and COL5A1) were identified, which were highly expressed in the left (LV) and right (RV) ventricles of HLH patients compared with controls. Furthermore, higher expression levels were detected in HLH patients with or without HF than in controls. Conclusion Our findings elucidate marker genes and molecular mechanisms of HLH, deepening the understanding of the pathogenesis of HLH.

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