Clinical Application of Stem Cells for Therapeutic Angiogenesis in Patients with Peripheral Arterial Disease

Abstract

Peripheral arterial disease (PAD) may ultimately cause to the loss of the affected limb due to gangrene or infection. Some patients with PAD may have severe coexisting diseases and diffuse involvement of their distal arteries, and so they are poor candidates for revascularization procedures. Angiogenesis has recently been suggested to be a new emerging treatment strategy for patients with PAD. Angiogenesis is defined as the sprouting of new capillaries from pre-existing vascular structures; this process plays a major role in the development of collateral vessels in an ischemic limb. Yet, the exact mechanism of angiogenesis is currently poorly understood. It has been established that angiogenesis is initiated by hypoxia and it requires various pro-angiogenic factors such as vascular endothelial growth factor. Therapeutic angiogenesis is aimed at enhancing natural angiogenesis by the administration of the cells or genes that can trigger angiogenesis and this can lead to pain relief and wound healing by the development of collateral vessels. Most of the recent clinical trials have reported that stem cell therapy for promoting angiogenesis in patients with PAD improves the ischemic symptoms and enhances wound healing. However, there are several limitations to approve a standard treatment for PAD such as small sample size in several prevous studies, their diverse inclusion criteria and the lack of standard assessment methods for the safety and outcome. Therefore, multicenter, large-scale and randomized controlled studies are needed to prove the safety and efficacy of the clinically applying stem cells for therapeutic angiogenesis in patients with PAD.

Coronary Collateral Growth: Clinical Perspectives and Recent Insights

“…Cardiomyocytes under the inluence of G-CSF-induced ROS generate angiogenic factors that lead to vascular growth and tube formation in levels comparative to cardiomyocytes induced by VEGF [61]. To the surprise of researchers, this study also demonstrated that G-CSF can promote coronary collateral growth without the impetus of repetitive ischemia and hence this cytokine can act as a surrogate for ischemia [61].Majority of the recent clinical trials in humans purport that stem cell-based therapy adequately facilitates angiogenesis in patients sufering from peripheral arterial disease and promotes wound healing [55]. Speciically, bone marrow-derived stem cell transplantation has shown to improve ischemic symptoms, such as claudication, ischemic rest pain, and has augmented wound healing in ulcer-related conditions [55].…”

“…Under certain physiologic and experimental conditions, they can be manipulated to grow into speciic tissues and organ cells with exclusive functionality. This revolutionary discovery for stem cells has demonstrated a clinical potential to create new networks of blood-perfused vessels and treat human patients with cardiovascular and vascular diseases [55]. The current theory is that stem cells may release a series of angiogenic factors, such as VEGF and bFGF, which mobilize vascular endothelial cells through a paracrine efect [56].…”

“…Majority of the recent clinical trials in humans purport that stem cell-based therapy adequately facilitates angiogenesis in patients sufering from peripheral arterial disease and promotes wound healing [55]. Speciically, bone marrow-derived stem cell transplantation has shown to improve ischemic symptoms, such as claudication, ischemic rest pain, and has augmented wound healing in ulcer-related conditions [55].…”

“…Nonetheless, these studies have been limited by a lack of care standardization, absence of a control group, small sample sizes, dissimilar inclusion criteria, and inconsistencies in methods of outcome assessment [55]. In other cases, the absence of follow-up procedures has prevented elucidation of long-term efects of treating peripheral artery disease with stem cells [55]. While the central issues of public safety and treatment eicacy linger over the ield, progress, albeit limited, has been made in the arena of coronary collateral growth.…”

“…Speciically, bone marrow-derived stem cell transplantation has shown to improve ischemic symptoms, such as claudication, ischemic rest pain, and has augmented wound healing in ulcer-related conditions [55]. Nonetheless, these studies have been limited by a lack of care standardization, absence of a control group, small sample sizes, dissimilar inclusion criteria, and inconsistencies in methods of outcome assessment [55]. In other cases, the absence of follow-up procedures has prevented elucidation of long-term efects of treating peripheral artery disease with stem cells [55].…”