Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Abstract

Cardiovascular disease (CVD) comprises a range of major clinical cardiac and circulatory diseases, which produce immense health and economic burdens worldwide. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. In turn, circulating endothelial colony-forming cells (ECFCs) represent truly endothelial precursors, which display high clonogenic potential and have the documented ability to originate de novo blood vessels in vivo. Therefore, ECFCs are regarded as the most promising cellular candidate to promote therapeutic angiogenesis in patients suffering from CVD. The current briefly summarizes the available information about the origin and characterization of ECFCs and then widely illustrates the preclinical studies that assessed their regenerative efficacy in a variety of ischemic disorders, including acute myocardial infarction, peripheral artery disease, ischemic brain disease, and retinopathy. Then, we describe the most common pharmacological, genetic, and epigenetic strategies employed to enhance the vasoreparative potential of autologous ECFCs by manipulating crucial pro-angiogenic signaling pathways, e.g., extracellular-signal regulated kinase/Akt, phosphoinositide 3-kinase, and Ca2+ signaling. We conclude by discussing the possibility of targeting circulating ECFCs to rescue their dysfunctional phenotype and promote neovascularization in the presence of CVD.

The human amniotic fluid stem cell secretome triggers intracellular Ca2+ oscillations, NF‐κB nuclear translocation and tube formation in human endothelial colony‐forming cells

“…Endothelial colony‐forming cells (ECFCs) represent vasculogenic cells that are truly committed to the endothelial lineage and, throughout postnatal life, are mobilized upon ischaemic injury to restore the damaged vascular network 1,2 . ECFCs possess a high clonogenic potential, form capillary‐like structures in in vitro Matrigel tubulogenesis assays, integrate into pre‐existing vasculature and rescue local blood perfusion in murine models of ischaemia 2,3 .…”

“…A more recent investigation showed that the hAFS secretome collected under hypoxic conditions stimulated circulating ECFCs to assemble into bidimensional capillary‐like networks in vitro through an oscillatory increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) 8,9 ; furthermore, it actively induced local angiogenesis and promoted cardiac repair in a murine model of AMI 8,9 . Therefore, the local injection of the hypoxic hAFS secretome could represent an alternative strategy to recruit circulating ECFCs towards the damaged myocardium and induce therapeutic angiogenesis 2 . The paracrine therapy of AMI would be promptly accessible to the patients and could overcome many of the drawbacks associated with cell‐based therapy, including the time‐consuming procedure and the requirement for huge amounts of cells 10,11 .…”

“… 1 , 2 ECFCs possess a high clonogenic potential, form capillary‐like structures in in vitro Matrigel tubulogenesis assays, integrate into pre‐existing vasculature and rescue local blood perfusion in murine models of ischaemia. 2 , 3 Therefore, ECFCs hold remarkable promise as the most suitable cellular substrate to induce therapeutic angiogenesis in ischaemic disorders, such as acute myocardial infarction (AMI), peripheral artery disease, and stroke. 2 , 3 , 4 Genetic manipulation and pharmacological conditioning could be exploited to improve ECFCs’ angiogenic activity and/or to improve their survival/engraftment within the harsh microenvironment of the ischaemic tissue.…”

Towards Novel Geneless Approaches for Therapeutic Angiogenesis

“…For instance, ECFC proliferation and tube formation are affected in the presence of elevated pro-inflammatory signaling ( Mena et al, 2018 ), oxidative stress ( Gremmels et al, 2017 ), and hypoxia ( He et al, 2018 ; Tasev et al, 2018 ). As recently reviewed ( Faris et al, 2020 ), the therapeutic use of umbilical cord blood-derived ECFCs, which display a greater pro-angiogenic potential as compared to circulating ECFCs, is currently not feasible for the high cost of their processing and banking and potential immune complications. It has, therefore, been proposed that the therapeutic outcome of ECFCs-based treatment of CVD could be remarkably improved by boosting the specific pro-angiogenic signaling pathways of circulating ECFCs ( Tasev et al, 2016 ; Moccia et al, 2018a , b ; Paschalaki and Randi, 2018 ).…”

Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro

“…The therapy mainly consists of vascular regenerative surgery and pharmacological therapy for alleviation, but not all patients benefit from current treatment options. Novel therapeutic approaches not only addressing the symptoms, but also the underlying pathological processes promoting neovascularization and vascular repair need to be developed [ 5 , 6 ].…”