Current concepts on endothelial stem cells definition, location, and markers

Abstract

Ischemic vascular disease is a major cause of mortality and morbidity worldwide, and regeneration of blood vessels in perfusion-deficient tissues is a worthwhile therapeutic goal. The idea of delivering endothelial stem/progenitor cells to repair damaged vasculature, reperfuse hypoxic tissue, prevent cell death, and consequently diminish tissue inflammation and fibrosis has a strong scientific basis and clinical value. Various labs have proposed endothelial stem/progenitor cell candidates. This has created confusion, as there are profound differences between these cell definitions based on isolation methodology, characterization, and reparative biology. Here, a stricter definition based on stem cell biology principles is proposed. Although preclinical studies have often been promising, results from clinical trials have been highly contradictory and served to highlight multiple challenges associated with disappointing therapeutic benefit. This article reviews recent accomplishments in the field and discusses current difficulties when developing endothelial stem cell therapies. Emerging evidence that disputes the classic view of the bone marrow as the source for these cells and supports the vascular wall as the niche for these tissue-resident endothelial stem cells is considered. In addition, novel markers to identify endothelial stem cells, including CD157, EPCR, and CD31^low VEGFR2^low IL33⁺ Sox9⁺ , are described.

Keywords: angiogenesis; blood vessels; circulating endothelial progenitor cells; endothelial colony-forming cells; endothelial stem cells; neovascularization; vascular repair.

FIGURE 1

Molecular identities reported for endogenous endothelial stem/progenitor cells. Diagram to depict endovascular progenitor cell types that reside within the vasculature and have vasoreparative properties reported in mouse tissues. Cell types shown in upper box. Cell surface markers shown in lower box. D cell, definitive differentiated; EVP, endovascular progenitor; TA, transit amplifying. Figure created in BioRender.com

FIGURE 2

PubMed search for original research articles investigating endothelial stem/progenitor cells. A, Bar plot for the frequency of publications in endothelial stem/progenitor cells or ECFCs from 2000 to 2020. B, Bar plot with taxonomy distribution for papers identified. C, UpSet plot to depict frequently used molecular markers or combinations in studies for endothelial stem/progenitor cells