Tm4sf1-marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension.
Jason HongBrenda WongCaroline HuynhBrian TangGregoire RuffenachMin LiSoban UmarXia YangMansoureh EghbaliPublished in: American journal of respiratory cell and molecular biology (2022)
The identification and role of endothelial progenitor cells (EPCs) in pulmonary arterial hypertension (PAH) remains controversial. Single-cell omics analysis can shed light on EPCs and their potential contribution to PAH pathobiology. We aim to identify endothelial cells that may have stem/progenitor potential in rat lungs and assess their relevance to PAH. Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA-seq of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic datasets. Rat lung endothelial cells were visualized by immunofluorescence in situ, analyzed by flow cytometry, and assessed for tubulogenesis in vitro. A subpopulation of endothelial cells (EA2) marked by Tm4sf1, a gene strongly implicated in cancer, harbored a distinct transcriptomic signature enriched for angiogenesis and CXCL12 signaling. Trajectory analysis predicted EA2 has a less differentiated state compared to other endothelial subpopulations. Analysis of independent datasets revealed TM4SF1 is downregulated in lungs and endothelial cells from patients and PAH models, is a marker for hematopoietic stem cells, and is upregulated in PAH circulation. TM4SF1+CD31+ rat lung endothelial cells were visualized in distal pulmonary arteries, expressed hematopoietic marker CD45 and formed tubules in co-culture with lung fibroblasts. Our study uncovered a novel Tm4sf1-marked subpopulation of rat lung endothelial cells that may have stem/progenitor potential and demonstrated its relevance to PAH. Future studies are warranted to further elucidate the role of EA2 and Tm4sf1 in PAH.
Keyphrases
- endothelial cells
- single cell
- rna seq
- pulmonary arterial hypertension
- pulmonary hypertension
- polycyclic aromatic hydrocarbons
- high glucose
- pulmonary artery
- stem cells
- high throughput
- vascular endothelial growth factor
- end stage renal disease
- flow cytometry
- human health
- genome wide
- copy number
- minimally invasive
- coronary artery
- risk assessment
- peritoneal dialysis
- chronic kidney disease
- ejection fraction
- cell therapy
- bone marrow
- newly diagnosed
- current status
- squamous cell
- transcription factor
- climate change
- squamous cell carcinoma
- dna methylation