Endothelial progenitor cells (EPCs) or angioblasts were originally thought to be present only during embryonic development. However, evidence accumuled over several years suggests that they can persist in adult life. This has generated interest in the use of angioblasts for neovascularization of ischemic or injured tissue and for the clinical assessment of risk factors for various diseases.
According to Dr Ralf Kolvenbach, Chief of the Department of General and Vascular Surgery at the Augusta Hospital Dusseldorf, Germany, bone marrow is a rich reservoir of tissue-specific stem and progenitor cells. Experimental and clinical studies have shown that angioblasts are mobilised from bone marrow, migrate to ischemic tissue, and contribute to the neovacularisation process in response to tissue ischemia.
In spite of the magnitude of papers published so far which document not only the feasibility but also the intermediate-term safety of stem cell therapy, primarily cardiologists are among those who have treated most patients with remarkable results. In 2002, investigators from Japan performed a prospective randomised controlled trial (entitled the ‘Therapeutic Angiogenesis by Cell Transplantation [TACT]’ study), in patients with peripheral arterial disease. They reported a significant increase in transcutaneous oxygen pressure, rest pain, and pain-free walking time after intramuscular injection of bone marrow-derived mononuclear cells.
In another recently published study, the efficacy and safety of autologous bone marrow-mononuclear cells (ABMMNC) implantation in patients with critical limb ischemia due to thromboangiitis obliterans (Buerger’s disease) was evaluated.
Preliminary clinical results
Thusfar, Kolvenbach and his colleagues have treated 15 patients with endstage critical ischemia with stem cells. In all cases after G-CSF mobilisation purified cells with CD 34 or CD 133 stem cells markers were injected directly into the ischemic limb. All cases presented a worst case scenario with a mean of three peripheral interventions or bypass procedures which had been performed prior to stem cell transplantation. Limb salvage rate was 70%, in two patients with progressive gangrene treatment was initiated too late.
“We also examined the growth of angioblast-colonies over a period of 14 days,” said Kolvenbach. “Colonies were picked up and analyzed by flow cytometrie. While CD34 and CD133 as stem cell markers disappeared until day four, expression of VEGFR-2 and CD144 increased until day eight of culture.”
At present it is unknown which cell type is the best to induce neovascularisation as treatment of peripheral artery disease. Therefore Kolvenbach used G-CSF mobilised peripheral blood stem cells. He explained that this is a very common, safe and simple method in the therapy of malignant hematopoietic diseases or solid tumors with several thousand patients treated worldwide so far. It allows the researchers to collect large numbers of cells. Stem cell injection can be performed as an outpatient or day surgery procedure.
Open questions and future perspectives
Several trials involving patients who present a worst case scenario have shown the efficacy and safety of stem cell therapy in critical limb ischemia. With few exceptions this novel treatment is offered by cardiologists and medical specialists to vascular patients. Some of them offering cellular therapy as an alternative to invasive treatment such as bypass surgery or angioplasty with enormous marketing implications.
According to Kolvenbach, there are still some open questions, such as which patient subset is best suited for cell based therapy? Kolvenbach explains that it is not known yet conclusively the exact mode of action of transplanted stem cells or angioblasts.
“From our own studies we infer that secretion of paracrine cytokines, such as VEGF and basic fibroblast growth factor (bFGF), is more essential than cell incorporation,” said Kolvenbach. “In a recent editorial in the NEJM [New England Journal of Medicine] Rosenzweig stated that ‘the understanding of any other mechanism of action of any therapeutic in the cardiovascular system is always provisional’. We are still trying to understand how aspirin and beta-blockers work,” said Kolvenbach. “Therefore we should not expect too much too soon.”
Despite these hurdles, the outlook for angioblast-based therapies for tissue ischemia and blood vessel repair appears promising, and the following points have been confirmed:
• Stem cell therapy is safe and can be offered to most patients with no or little side effects.
• So far its use was restricted to patients with critical ischemia, in the future treatment of claudicants will be another option.
• This kind of molecular treatment will be the most less invasive way of therapy we will be able to offer to our patients.