Description of the condition
Peripheral arterial disease (PAD) affects 3% to 10% of the population (Norgren 2010). It is a prevalent health problem all over the world and is associated with a significant burden in terms of morbidity and mortality, due to intermittent claudication and critical limb ischaemia (CLI). Intermittent claudication is the most common form of PAD and is generally managed conservatively. CLI is a more severe form of PAD and is characterised by rest pain, ulcerations, and gangrene. Revascularisation, either surgical or endovascular, aiming to improve blood flow to the affected extremity is the gold standard therapy for patients with severe PAD. However, this treatment modality cannot be applied to over 30% of patients because of excessive operative risk and unfavourable vascular involvement (Sasajima 1997). Moreover, revascularisation may not be successful owing to the presence of extensive atherosclerotic plaque and the low rates of long-term patency in severe PAD (Conrad 2011). Hence, many patients are reliant on medical therapy that may only slow disease progression temporarily and the only remaining option for relief of pain or treatment of gangrene is amputation of the affected limb (Botti 2012). Of note, after one year, 30% of patients with CLI undergo amputation (Norgren 2007). An estimated 120 to 150 amputations are performed per million people per year, and one-quarter of these patients require long-term institutional care or professional assistance at home (Norgren 2007). There is a critical need to develop novel strategies to promote vascular regeneration (neovascularisation) in patients with CLI who are not suitable for conventional treatments. The current literature suggests that stem cell therapy is a relatively safe, feasible, and possibly effective therapy for patients with CLI, and stem cells may be considered as an alternative treatment for patients who are not suitable for revascularisation and best medical therapy.
Description of the intervention
Although initial clinical studies on stem cell therapy have been encouraging, current evidence from large scale randomised controlled clinical trials (RCTs) comparing active treatment with placebo is limited, leading to a previous Cochrane review concluding that there was "insufficient evidence to support cell therapy in clinical practice" (Moazzami 2011). The procedures are generally safe and well tolerated and there have been extensive clinical studies involving patients with PAD utilising stem cells derived from various sources. The types of cells used for implantation to date have been bone marrow (BM) mononuclear cells (BM-MNCs) (Durdu 2006; Miyamoto 2006; Tateishi-Yuyama 2002), peripheral blood mononuclear cells (PB-MNCs) (Huang 2004; Kawamura 2006; Lenk 2005; Matsui 2003), granulocyte colony-stimulating factor (G-CSF)-mobilised PB-MNCs (M-PBMNC) (Huang 2005; Huang 2007; Ishida 2005), CD34 antigen-positive MNCs (Inaba 2002; Kawamoto 2009), CD133 antigen-positive MNCs (Burt 2010), BM-mesenchymal stem cells (BM-MSCs) (Dash 2009; Lu 2011). and recently in small series of patients adipose tissue-MSCs (AT-MSCs) (Lee 2012). Implantation of cells into patients via several routes including intramuscular, intra-arterial, or a combination of both, have yielded promising results in patients with PAD. Intramuscular injection is usually performed through multiple injections at the level of the gastrocnemius muscles, while intra-arterial infusion is usually performed via the femoral artery. MNCs and stem cells derived from different sources may have different clinical outcomes in patients with PAD. Stem cells obtained from different sources may vary in biological (plasticity, self renewal, differentiation, homing, migration, secretion of trophic factors) and immunological (modulating immune response) properties. This may be attributed to the inherent biological properties of the stem cells or changes to the cells that may occur during cell enrichment and culture. For example, injection of G-CSF that is used to mobilise BM-derived progenitor cells can significantly enhance the formation of several growth factors involved in vascular repair (Huang 2007). In addition, the apheresis procedure results in the transient cleavage of the chemokine receptor (directly involved in stem cell homing) from M-PBMNCs (Honold 2006).
How the intervention might work
To date, the mechanisms by which the transplanted cells improve clinical outcomes in patients with PAD are still unclear. Experimental animal studies indicate that BM-derived cells contribute to vascular and muscle regeneration by physically integrating into the tissue or by secreting growth factors, or both (Fadini 2007; Honold 2006). BM adult stem cells with angiogenic potential such as endothelial progenitor cells (EPCs) and MSCs have the capability to stimulate the formation of new blood vessels (Schatteman 2004). MSCs are reported to promote angiogenesis because of their capacity to differentiate into endothelial cells (ECs) and vascular smooth muscle (Pittenger 1999; Reyes 2002) and to stimulate EC proliferation and migration. EPCs have direct angiogenic action, supporting angiogenesis through their ability to secrete paracrine mediators (Jarajapu 2010). Furthermore, MSCs support neo-angiogenesis by releasing soluble factors that stimulate EPCs sprouting from pre-existing blood vessels (Cobellis 2010; Jarajapu 2010). Therefore, cell transplantation into ischaemic limbs may promote neo-angiogenesis by providing precursor cells capable of vascular transdifferentiation, and by supplying multiple angiogeneic cytokines, growth factors and homing signals for mural cells or pericytes for microvascular stabilisation (Benoit 2013; Kaelin 2008). The combination of these mechanisms is responsible for augmenting vascular repair and ameliorating tissue perfusion, which leads to reversal of ischaemia of the affected limb.
Why it is important to do this review
It is important to do this review to determine whether different sources or methods of MNC and stem cell preparation have different effects on clinical outcomes following transfer into CLI patients; and whether a combination versus a single type of MNC or stem cell treatment improves ischaemic symptoms and survival in patients with CLI. Currently the data comparing the angiogenic potency of cells derived from different sources are limited. Questions regarding the optimal cell dose, cell phenotype, cell processing, route of delivery, and frequency of application remain open. The current proposed meta-analysis attempts to address some of these challenging issues based on the published data on cell therapy trials in patients with PAD. Obtaining a comprehensive insight to these key points is critical in designing the optimal cell-based therapy program for patients with CLI as well as in identifying critical areas for improvement and in making recommendations for future clinical trials. Additionally, other sources of stem cells might become available such as placenta and stored autologous cord blood. It is not yet known whether cells from these sources would be as effective as cells derived from BM or PB in treating CLI and studies involving cells from new sources will be included in future updates.