Recent Advances in Endothelial Progenitor Cells Toward Their Use in Clinical Translation

Abstract

Since the discovery of Endothelial Progenitor Cells (EPC) by Asahara and colleagues in 1997, an increasing number of preclinical studies have shown that EPC based therapy is feasible, safe, and efficacious in multiple disease states. Subsequently, this has led to several, mainly early phase, clinical trials demonstrating the feasibility and safety profile of EPC therapy, with the suggestion of efficacy in several conditions including ischemic heart disease, pulmonary arterial hypertension and decompensated liver cirrhosis. Despite the use of the common term “EPC,” the characteristics, manufacturing methods and subset of the cell type used in these studies often vary significantly, rendering clinical translation challenging. It has recently been acknowledged that the true EPC is the endothelial colony forming cells (ECFC). The objective of this review was to summarize and critically appraise the registered and published clinical studies using the term “EPC,” which encompasses a heterogeneous cell population, as a therapeutic agent. Furthermore, the preclinical data using ECFC from the PubMed and Web of Science databases were searched and analyzed. We noted that despite the promising effect of ECFC on vascular regeneration, no clinical study has stemmed from these preclinical studies. We showed that there is a lack of information registered on www.clinicaltrials.gov for EPC clinical trials, specifically on cell culture methods. We also highlighted the importance of a detailed definition of the cell type used in EPC clinical trials to facilitate comparisons between trials and better understanding of the potential clinical benefit of EPC based therapy. We concluded our review by discussing the potential and limitations of EPC based therapy in clinical settings.

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

“…Yet, they are far from being probed in clinical trials on ischemic patients. A recent article surveyed the clinical studies that probed EPCs as a therapeutic agent against an array of pathologies [ 111 ]. Only 26 out of 341 clinical trials identified by searching the term “EPC” assessed the regenerative outcome of EPCs in severe ischemic disorders, such as CAD, PAD, and stroke, whereas the remaining investigations were of a more observational nature (i.e., they evaluated EPC levels as biomarkers for different pathological conditions).…”

“…Only 26 out of 341 clinical trials identified by searching the term “EPC” assessed the regenerative outcome of EPCs in severe ischemic disorders, such as CAD, PAD, and stroke, whereas the remaining investigations were of a more observational nature (i.e., they evaluated EPC levels as biomarkers for different pathological conditions). Five additional trials, which were identified through a search on PubMed and Web of Science databases, were conducted to examine the impact of EPCs-based therapy in PAD, CAD, pulmonary hypertension, and liver cirrhosis [ 111 ]. These studies demonstrated that EPC therapy was feasible and safe; however, it was concluded that the EPC populations employed, deriving either from bone marrow or UCB, were largely heterogenous and mainly consisted of hematopoietic angiogenic cells, such as MACs [ 33 , 111 ].…”

“…Five additional trials, which were identified through a search on PubMed and Web of Science databases, were conducted to examine the impact of EPCs-based therapy in PAD, CAD, pulmonary hypertension, and liver cirrhosis [ 111 ]. These studies demonstrated that EPC therapy was feasible and safe; however, it was concluded that the EPC populations employed, deriving either from bone marrow or UCB, were largely heterogenous and mainly consisted of hematopoietic angiogenic cells, such as MACs [ 33 , 111 ]. Surprisingly, no clinical trial has yet assessed the therapeutic efficacy and feasibility of ECFCs as cellular substrate to treat ischemic disorders.…”

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

“…Yet, they are far from being probed in clinical trials on ischemic patients. A recent article surveyed the clinical studies that probed EPCs as therapeutic agent against an array of pathologies [121]. Only 26 out of 341 clinical trials identified by searching the term "EPC" assessed the regenerative outcome of EPCs in severe ischemic disorders, such as CAD, PAD and stroke, whereas the remaining investigations were of more observational nature (i.e.…”

Endothelial progenitor cell dysfunction in diabetes mellitus: new target for risk stratification and therapies?

“…Thus, EPCs are determined as a component of endogenous vascular repair system that supports vascular integrity, endothelial function, angiogenesis, neovascularization and reparation [5]. There is a large of body evidence that decreased number and / or weak function of EPCs known as EPC dysfunction frequently proceeded to developing cardiovascular (CV) disease and / or CV events and also accompanied CV risk factors [6][7][8]. Indeed, declined number of circulating EPCs was associated with CV complications, but restoring of a pole of angiopoetic endothelial precursors was related to an attenuation of vascular function, decreasing of a risk of CV events and improving of clinical outcomes [9,10].…”