CD34-positive stem cells: in the treatment of heart and vascular disease in human beings

Abstract

Bone marrow-derived CD34(+) cells are a well-characterized population of stem cells that have traditionally been used clinically to reconstitute the hematopoietic system after radiation or chemotherapy. More recently, CD34(+) cells have also been shown to induce therapeutic angiogenesis in animal models of myocardial, peripheral, and cerebral ischemia. The mechanism by which CD34(+) cells promote therapeutic angiogenesis is not completely understood, although evidence supports both direct incorporation of the cells into the expanding vasculature and paracrine secretion of angiogenic growth factors that support the developing microvasculature. Phase I and phase II clinical trials have explored the usefulness of CD34(+) cells in the treatment of ischemic conditions in human patients. As the population of patients diagnosed with some form of ischemic cardiovascular disease expands, the need for more effective treatments also grows, especially in patients who are refractory to standard pharmacologic or revascularization treatment. As phase III trials begin, CD34(+) cells will be definitively tested as a novel treatment for myocardial and peripheral ischemia. This review will discuss what is known about the CD34 antigen and the cells that harbor it, the preclinical evidence supporting the therapeutic potential of CD34(+) cells in ischemic models, and, last, the current evidence for the clinical usefulness of CD34(+) cells in the treatment of human ischemic disease.

Trial registration: ClinicalTrials.gov NCT00535197 NCT00761982 NCT00950521 NCT01019733.

Keywords: Angiogenesis; antigens, CD34; bone marrow cells; brain ischemia; brain/blood supply; cell adhesion; cell movement; cerebral infarction; endothelial cells; extremities/blood supply; hematopoietic stem cell mobilization; hematopoietic stem cell transplantation; ischemia/therapy; myocardial ischemia; nanofibers; neovascularization, physiologic; peripheral blood stem cell transplantation; regeneration; stem cells; tissue repair.

Fig. 1 This illustration shows the basic methodology of CD34⁺ cell treatment for ischemic conditions. Unlike conventional pharmacologic therapies, autologous cell-based therapies require that patients have their cells harvested before treatment, which involves the administration of a cell-mobilizing agent. After a short course of the mobilizing agent (1 injection/d for 3–5 d), leukoapheresis is performed for the collection of mononuclear cells from peripheral blood. The CD34⁺ cell population can then be purified using immuno-based selection techniques. Once purified, the CD34⁺ cells are subjected to testing and are generally required to meet lot-release criteria, which include sterility, viability, absence of endotoxin, as well as CD34⁺ cell content. Once the cells have passed the lot-release criteria, they are then handled and administered by methods that are appropriate and specific to the ischemic condition being treated. BMMNC = bone marrow mononuclear cells