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Critical Limb Ischemia
 - Cell Therapy Approaches

Peripheral arterial disease (PAD) develops upon ischemia of the limbs secondary to atherosclerotic occlusion. Critical limb ischemia (CLI) is the most advanced stage of PAD, and is caused by chronic inflammatory processes associated with atherosclerosis.  CLI patients present markedly reduced blood flow to the legs, feet and hands, manifested by ischemic rest pain or tissue loss. Therapeutic goals in treating CLI patients include reducing cardiovascular risk factors, relieving ischemic pain, healing ulcers, preventing major amputation, improving quality of life and increasing survival. Current treatment options for CLI include bypass surgery or endovascular revascularization. However, approximately 20–30% of patients with CLI are poor candidates for such interventions, due to anatomical limitations, such as poor outflow vessels, extensive comorbidities, or previously failed revascularization attempts, often leaving amputation as the only option available.

Cell Therapy Approaches

Recently, research efforts have concentrated on cell-based therapies for CLI that aim to improve limb perfusion by enhancing neovascularization.

Endothelial progenitor cells (EPCs) are characterized by CD34 expression; CD34+ cells comprise 1% of the total peripheral mononuclear cells (MNCs) population. Coculture of CD34+ and the remaining CD34− MNCs resulted in greater proliferation and differentiation of endothelial cells than with CD34+ alone, indicating that this marker taken in isolation may not identify all cellular elements involved in vasculogenesis. Thus, novel markers of stem cells, such as intracellular enzymes shared by multiple progenitor lines, are being under research, such as aldehyde dehydrogenase–expressing cells. To date, no single cell-surface marker has been found to specifically identify all EPCs, and no single cell source, culture, or selection method, dosing regimen, or route of administration has been clearly proven superior to others in their therapeutic impact.  As a result, the ongoing studies of therapeutic vasculogenesis are quite heterogeneous in both research design and methods of endpoint measurements. A variety of EPC sources have been applied, including bone morrow, peripheral blood, unselected mesenchyme, adipose tissue, and umbilical cord blood.

Many clinical trials have investigated the safety and efficacy of EPCs in the treatment of PAD. EPCs can be administered either as a subpopulation of unselected MNCs or following cell surface-antigen-directed selection of specific populations, such as CD34+, CD133 and CD31+ cells. Typical routes of delivery are direct intramuscular and intra-arterial injection.

The majority of trials to date have used either bone marrow-derived mononuclear cells (BM-MNCs) or peripheral blood-derived MNCs. The initial landmark TACT trial showed, for the first time, that autologous BM-MNCs can safely and effectively achieve therapeutic neovascularization in CLI patients. It has been shown that BM-MNCs promoted collateral vessel formation in patients with severe PAD.

The BM-MNCs from patients with CLI have evidence of an impaired phenotype and a lower number of endothelial progenitor cells compared to the normal population or to patients with Buerger’s Disease. Multiple strategies have been employed to mobilize and derive cells to improve the performance of cell therapy in CLI, including intra-arterial or intra-muscular administration of BM-MNCs or peripheral blood mononuclear cells (PB-MNC). A meta-analysis of 37 clinical trials utilizing autologous bone marrow or granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood cells for treatment of CLI patients, has been conducted. Autologous cell therapy was shown to be effective in improving surrogate indexes of ischemia, subjective symptoms, and hard endpoints (ulcer healing and amputation). In contrast, G-CSF monotherapy was not associated with significant improvement of these same endpoints. The intramuscular route of administration and the use of bone marrow cells seemed more effective than intra-arterial administration and use of mobilized peripheral blood cells.

In conclusion, intramuscular autologous bone marrow cell therapy is a feasible, relatively safe, and potentially effective therapeutic strategy for PAD patients who are poor candidates for traditional revascularization, or when such interventions are contraindicated altogether.

Critical Limb Ischemia