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A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Authors :
Yiping Sun
Xueqing Hu
Kui Zhang
Man Rao
Pengbin Yin
Ran Dong
Source :
Cells, Vol 11, Iss 17, p 2711 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Background: The great saphenous vein (GSV) is the most commonly used conduit for coronary arterial bypass graft. However, the status of the GSV, including metabolic dysfunction such as diabetes mellitus (DM) complication, is strongly associated with vein graft failure (VGF). To date, the molecular mechanism underlying VGF remains elusive. Detailed characterization of the cellular components and corresponding expression regulation in GSVs would be of great importance for clinical decision making to reduce VGF. Methods: To this end, we performed single-cell RNA sequencing to delineate cellular heterogeneity in three human GSV samples. Results: Scrutinization of cellular composition and expression revealed cell diversity in human GSVs, particularly endothelial cells (ECs). Our results unraveled that functional adaptation drove great expression differences between venous ECs and valvular ECs. For instance, cell surface receptor ACKR1 demarcated venous Ecs, whereas ACRK3/ACKR4 were exclusively expressed by valvular ECs. Differential gene expression analysis suggested that genes highly expressed in venous ECs were mainly involved in vasculature development and regulation of leukocyte adhesion, whereas valvular ECs have more pronounced expression of genes participating in extracellular matrix organization, ossification and platelet degranulation. Of note, pseudo-time trajectory analysis provided in silico evidence indicating that venous ECs, valvular ECs and lymphatic vessels were developmentally connected. Further, valvular ECs might be an importance source for lymphatic vessel differentiation in adults. Additionally, we found a venous EC subset highly expressing IL6, which might be associated with undesirable prognosis. Meanwhile, we identified a population of ANGPTL7+ fibroblasts (FBs), which may be profibrotic and involved in insulin resistance in human GSVs. Additionally, our data suggest that immune cells only accounted for a small fraction, most of which were macrophages. By assessing the intertwined remodeling in metabolic dysfunction that potentially increases the gene expression regulatory network in mural cells and leukocytes, we found that transcription factor KLF9 likely operated a proinflammatory program, inducing the transcription of metallothionein proteins in two mural cell subsets and proinflammatory immune cells. Lastly, cellular communication analysis revealed that proinflammatory signaling, including TRAIL, PVR, CSF and GDF, were uniquely activated in patients with metabolic dysfunction. Conclusions: Our results identified critical cell-specific responses and cellular interactions in GSVs. Beyond serving as a repertoire, this work illustrates multifactorial likelihood of VGF.

Details

Language :
English
ISSN :
11172711 and 20734409
Volume :
11
Issue :
17
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.11a149712cfa41b08685ab1bade05dfd
Document Type :
article
Full Text :
https://doi.org/10.3390/cells11172711