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.

Keywords: cardiovascular disease; endothelial colony forming cells; genetic modification; ischemic disorders; pharmacological conditioning; signaling pathways; therapeutic angiogenesis.

Figure 1

Manipulating dysfunctional endothelial colony-forming cells (ECFCs) to improve their regenerative potential for therapeutic angiogenesis. ECFCs isolated from the peripheral blood of individuals suffering from cardiovascular disease (CVD) present a reduced therapeutic efficacy. A number of strategies were designed to improve the regenerative potential of these ECFCs in the view of autologous cell-based therapy. These treatments include pharmacological pre-conditioning (e.g., with bioactive cues), genetic manipulation, and epigenetic activation, to improve their pro-angiogenic potential. It has been shown that ECFC manipulation remarkably improves neovascularizaiton and restores local blood flow in animal models of acute myocardial infarction (AMI), ischemic retinopathy, peripheral artery disease (PAD), and stroke.