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RNA-seq analysis of human expandable arterial endothelial precursors (eAEPs), expandable mesenchymal precursors (eMPs), and controls

ABSTRACT: The following is an excerpt from the abstract of Miller et al. In this study, we find that two transcription factors, MYCN and SOX17, enable the indefinite propagation of human endothelial arterial precursors in vitro (“expandable arterial endothelial precursors,” eAEPs). Independent eAEP lines differ in their proclivity to undergo an endothelial-to-mesenchymal transition (EndoMT), a hallmark event in a broad array of vascular diseases and disorders. Some lines spontaneously become mesenchymal over time in culture, an effect exacerbated by inhibition of the fibroblast growth factor (FGF) receptor, while others do not readily convert. These distinctions were exploited to identify genes that correlate with resistance to an EndoMT and to elucidate transcriptional changes that underpin the transition. We believe the eAEPs may be useful not only as tractable tools for biological or pathological studies, but also as platforms for drug discovery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106991 | GEO | 2018/01/09

SECONDARY ACCESSION(S): PRJNA418736

REPOSITORIES: GEO

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Project description:Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue. Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP+. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals. Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFb signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-⍺ exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT. These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity.

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RNA-seq analysis of human expandable arterial endothelial precursors (eAEPs), expandable mesenchymal precursors (eMPs), and controls

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