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.
Highlights
Cardiovascular disease (CVD) comprises a group of heart and circulatory disorders, which are regarded as a global medical and economic issue with high prevalence and mortality rates [1]
The current review provides a brief outline on the origin and characterization of endothelial colony-forming cells (ECFCs) and a summary of the progress in preclinical studies aiming at assessing their efficacy in a variety of ischemic disorders, including acute myocardial infarction (AMI), peripheral arterial disease (PAD), ischemic brain disease, and retinopathy (Figure 1)
The reinoculation of autologous ECFCs requires the development of protocols compatible with the good manufacturing practice (GMP) for cell-based therapies and the use of xeno-free culture media, e.g., platelet lysate (Section 3.1), to achieve their expansion [50,70]
Summary
Cardiovascular disease (CVD) comprises a group of heart and circulatory disorders, which are regarded as a global medical and economic issue with high prevalence and mortality rates [1]. Stem cells may efflux Hoechst 33,342 at a faster rate as compared to differentiated cells [49] due to the higher expression of a novel stem cell marker, the ABC-binding cassette transporter ABCG2 These endothelial–SP cells were dispersed along the vascular tree, showed robust proliferative potential, and were able to promote neovascularization and rescue blood perfusion in mouse models of hindlimb ischemia [47]. It is unclear whether circulating ECFCs are contributed by VESCs sloughed off from the vascular wall as well, as it remains to be fully established that they are mobilized from the vascular niches following an ischemic insult. ECFCs proliferate and engraft within the injured endothelium to promote vascular repair, possibly in combination with the secretion of trophic mediators
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