Autologous Transplantation of Granulocyte Colony–Stimulating Factor–Mobilized Peripheral Blood Mononuclear Cells Improves Critical Limb Ischemia in Diabetes

Abstract

OBJECTIVE -To assess the application of autologous transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMNCs) in the treatment of critical limb ischemia (CLI) of diabetic patients and to evaluate the safety, efficacy, and feasibility of this novel therapeutic approach. RESEARCH DESIGN AND METHODS -Twenty-eight diabetic patients with CLIwere enrolled and randomized to either the transplant group or the control group. In the transplant group, the patients received subcutaneous injections of recombinant human G-CSF (600 g/day) for 5 days to mobilize stem/progenitor cells, and their PBMNCs were collected and transplanted by multiple intramuscular injections into ischemic limbs. All of the patients were followed up after at least 3 months.RESULTS -At the end of the 3-month follow-up, the main manifestations, including lower limb pain and ulcers, were significantly improved in the patients of the transplant group. Their laser Doppler blood perfusion of lower limbs increased from 0.44 Ϯ 0.11 to 0.57 Ϯ 0.14 perfusion units (P Ͻ 0.001). Mean ankle-brachial pressure index increased from 0.50 Ϯ 0.21 to 0.63 Ϯ 0.25 (P Ͻ 0.001). A total of 14 of 18 limb ulcers (77.8%) of transplanted patients were completely healed after cell transplantation, whereas only 38.9% of limb ulcers (7 of 18) were healed in the control patients (P ϭ 0.016 vs. the transplant group). No adverse effects specifically due to cell transplantation were observed, and no lower limb amputation occurred in the transplanted patients. In contrast, five control patients had to receive a lower limb amputation (P ϭ 0.007, transplant vs. control group). Angiographic scores were significantly improved in the transplant group when compared with the control group (P ϭ 0.003).CONCLUSIONS -These results provide pilot evidence indicating that the autologous transplantation of G-CSF-mobilized PBMNCs represents a simple, safe, effective, and novel therapeutic approach for diabetic CLI. Diabetes Care 28:2155-2160, 2005D iabetes is a common chronic disease with significant morbidity and mortality. One devastating complication of diabetes is peripheral arterial disease (PAD) including critical limb ischemia (CLI), which may result in limb loss. There is no available permanent cure for diabetic CLI at present (1,2).Several investigations have indicated that in patients with diabetes, the circulating endothelial progenitor cells (EPCs) exhibit impaired proliferation, adhesion, and incorporation into vascular structures. The adverse metabolic stress factors are associated with reduced number and dysfunction of EPCs (3,4). In response to tissue injury and remodeling, neovascularization usually occurs via the proliferation and migration of endothelial cells from preexisting vasculature (5). However, the EPCs resident within bone marrow and peripheral blood (6 -8) can also contribute to injury-induced and pathology-induced neovascularization. In animal models of diabetes, transplantation of bone marrow-or blood-derived EPC...

Oxidized Low-Density Lipoprotein Induces Apoptosis in Endothelial Progenitor Cells by Inactivating the Phosphoinositide 3-Kinase/Akt Pathway

“…Indeed, studies in mice [35] as well as controlled human trials [36] support the feasibility of autologous EPC transplantation wherein EPCs would be harvested, expanded ex vivo, and then transfused back into the patient. A clear impediment to this approach, however, is that underlying diseases can impair the integrity of EPCs and thus potentially render them ineffective for autologous transfusion [37].…”

Oxidative Stress, Endothelial Function and Angiogenesis Induced by Cell Therapy and Gene Therapy

“…Unfortunately, patients with PAD with no other treatment option are subjected to amputation. However, recent studies have shown that cell therapy or gene therapy increases collateral vessel formation in ischemic limb models [22][23][24][25][26][27][28][29][30][31][32] and in patients with limb ischemia who have no other treatment option [33][34][35][36][37][38][39][40][41][42][43][44][45][46]. Both cell and gene therapy improve not only limb ischemic symptoms and findings of angiography but also endothelial function in patients with limb ischemia [38,44].…”

Stem Cell Therapy in Patients with Thromboangiitis Obliterans: Assessment of the Long-Term Clinical Outcome and Analysis of the Prognostic Factors

“…Third, the ideal source and types of stem cells and their amount and route of administration have not been established. Most of all, as a source of stem Increased diameter and length of the pre-existing collateral vessels cells, the majority of studies used autologous bone marrow-derived or peripheral blood-derived mononuclear cells (3,(5)(6)(7)(8). However, the isolation of mononuclear cells from bone marrow or peripheral blood is highly complex and expensive and there is a potential danger of contamination.…”