RT Journal Article
SR Electronic
T1 A <em>Tm4sf1</em>-Marked Subpopulation of Endothelial Stem/Progenitor Cells Identified by Lung Single-Cell Omics of Pulmonary Arterial Hypertension
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.09.475566
DO 10.1101/2022.01.09.475566
A1 Hong, Jason
A1 Wong, Brenda
A1 Huynh, Caroline
A1 Tang, Brian
A1 Umar, Soban
A1 Yang, Xia
A1 Eghbali, Mansoureh
YR 2022
UL http://biorxiv.org/content/early/2022/01/11/2022.01.09.475566.abstract
AB Rationale 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.Objectives We aim to identify EPCs in rat lungs and assess their relevance to preclinical and human PAH.Methods 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.Measurements and Main Results A subpopulation of endothelial cells (EA2) marked by Tm4sf1, a gene strongly implicated in cancer, harbored a distinct transcriptomic signature including Bmpr2 downregulation that was enriched for pathways such as inflammation and angiogenesis. Cell-to-cell communication networks specific to EA2 were activated in PAH such as CXCL12 signaling. Trajectory analysis demonstrated EA2 has a stem/progenitor cell phenotype. Analysis of independent datasets revealed Tm4sf1 is a marker for hematopoietic stem cells and is upregulated in PAH peripheral blood, particularly in patients with worse WHO functional class. EA2 signature genes including Procr and Sulf1 were found to be differentially regulated in the lungs of PAH patients and in PAH models in vitro, such as BMPR2 knockdown.Conclusions Our study uncovered a novel Tm4sf1-marked stem/progenitor subpopulation of rat lung endothelial cells and demonstrated its relevance to preclinical and human PAH. Future experimental studies are warranted to further elucidate the pathogenic role and therapeutic potential of targeting EA2 and Tm4sf1 in PAH.Competing Interest StatementThe authors have declared no competing interest.