Human endothelial colony-forming cells in regenerative therapy: A systematic review of controlled preclinical animal studies

Abstract

Endothelial colony-forming cells (ECFCs) hold significant promise as candidates for regenerative therapy of vascular injury. Existing studies remain largely preclinical and exhibit marked design heterogeneity. A systematic review of controlled preclinical trials of human ECFCs is needed to guide future study design and to accelerate clinical translation. A systematic search of Medline and EMBASE on 1 April 2019 returned 3131 unique entries of which 66 fulfilled the inclusion criteria. Most studies used ECFCs derived from umbilical cord or adult peripheral blood. Studies used genetically modified immunodeficient mice (n = 52) and/or rats (n = 16). ECFC phenotypes were inconsistently characterized. While >90% of studies used CD31+ and CD45−, CD14 − was demonstrated in 73% of studies, CD146+ in 42%, and CD10+ in 35%. Most disease models invoked ischemia. Peripheral vascular ischemia (n = 29), central nervous system ischemia (n = 14), connective tissue injury (n = 10), and cardiovascular ischemia and reperfusion injury (n = 7) were studied most commonly. Studies showed predominantly positive results; only 13 studies reported ≥1 outcome with null results, three reported only null results, and one reported harm. Quality assessment with SYRCLE revealed potential sources of bias in most studies. Preclinical ECFC studies are associated with benefit across several ischemic conditions in animal models, although combining results is limited by marked heterogeneity in study design. In particular, characterization of ECFCs varied and aspects of reporting introduced risk of bias in most studies. More studies with greater focus on standardized cell characterization and consistency of the disease model are needed.

Current Concepts on Endothelial Stem Cells Definition, Location, and Markers

“… 19 A systematic review of controlled preclinical animal studies using human ECFCs concluded that while the potential clinical application for ECFCs is evolving rapidly, the wider implementation of already established standardized ECFC characterization will enable more rapid and effective transition to clinical trials. 20 …”

Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice

“…ECFCs are primary human ECs that reside in the blood vessels of human individuals, circulate in very low numbers in peripheral blood, and display a hierarchy of clonal proliferative potential and in vivo vessel-forming ability ( 18 , 19 ). ECFCs have been purported to be a potential source of reparative cells for ischemic disorders in human individuals ( 20 , 21 ). Unfortunately, access to primary ECFCs is severely limited by location, rarity in circulating blood, reductions in blood concentration with aging, and risk of dysfunction in disorders, such as diabetes ( 22 , 23 ).…”

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

“…Issues related to cell product characterization are not unique to MSC based studies. A systematic review examining the use of endothelial colony‐forming cells (ECFCs as a therapeutic intervention in preclinical animal models found that very few studies characterized their ECFCs according to established minimal standards [75] . Strengthening the reporting and adherence to standardized product characterization should reduce heterogeneity and improve confidence in study results from cell therapy studies.…”