Red Blood Cell Contamination of the Final Cell Product Impairs the Efficacy of Autologous Bone Marrow Mononuclear Cell Therapy

• Published in: Journal of the American College of Cardiology Vol. 55; no. 13; pp. 1385 - 1394
• Main Authors: Assmus, Birgit, MD, Tonn, Torsten, MD, Seeger, Florian H., MD, Yoon, Chang-Hwan, MD, Leistner, David, MD, Klotsche, Jens, MSc, Schächinger, Volker, MD, Seifried, Erhard, MD, Zeiher, Andreas M., MD, Dimmeler, Stefanie, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 30.03.2010; Elsevier; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Bone marrow; Bone Marrow Transplantation - methods; Cardiology; Cardiology. Vascular system; Cardiovascular; Cell Count; Cell Separation - methods; Cell Separation - standards; Cell Survival; Disease Models, Animal; Erythrocytes; Heart attacks; Hindlimb - blood supply; Humans; Internal Medicine; Ischemia - therapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Multivariate Analysis; Myocardial Contraction - physiology; myocardial infarction; Myocardial Infarction - therapy; progenitor cells; Quality Control; REPAIR-AMI trial; Stem Cell Transplantation; Stem cells; Stroke Volume; Studies; Treatment Outcome; NO; nitric oxide; REPAIR-AMI trial; bone marrow mononuclear progenitor cell; myocardial infarction; LVEF; progenitor cells; stromal cell-derived factor; LV; FACS; red blood cell (erythrocyte); left ventricular ejection fraction; RBC; CFU; SDF; fluorescent-activated cell sorting; BMC; colony-forming unit; left ventricle/ventricular; AMI; acute myocardial infarction; Mononuclear cell; Treatment; Efficiency; Red blood cell; Bone marrow; Product; Autologous system; Circulatory system; Cardiology; Cell; Contamination
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.10.059

Objectives The aim of this study was to identify an association between the quality and functional activity of bone marrow-derived progenitor cells (BMCs) used for cardiovascular regenerative therapies and contractile recovery in patients with acute myocardial infarction included in the placebo-controlled REPAIR-AMI (Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction) trial. Background Isolation procedures of autologous BMCs might affect cell functionality and therapeutic efficacy. Methods Quality of cell isolation was assessed by measuring the total number of isolated BMCs, CD34+ and CD133+ cells, their colony-forming unit (CFU) and invasion capacity, cell viability, and contamination of the final BMC preparation with thrombocytes and red blood cells (RBCs). Results The number of RBCs contaminating the final cell product significantly correlated with reduced recovery of left ventricular ejection fraction 4 months after BMC therapy (p = 0.007). Higher numbers of RBCs in the BMC preparation were associated with reduced BMC viability (r = −0.23, p = 0.001), CFU capacity (r = −0.16, p = 0.03), and invasion capacity (r = −0.27, p < 0.001). To assess a causal role for RBC contamination, we coincubated isolated BMCs with RBCs for 24 h in vitro. The addition of RBCs dose-dependently abrogated migratory capacity (p = 0.003) and reduced CFU capacity (p < 0.05) of isolated BMCs. Neovascularization capacity was significantly impaired after infusion of BMCs contaminated with RBCs, compared with BMCs alone (p < 0.05). Mechanistically, the addition of RBCs was associated with a profound reduction in mitochondrial membrane potential of BMCs. Conclusions Contaminating RBCs affects the functionality of isolated BMCs and determines the extent of left ventricular ejection fraction recovery after intracoronary BMC infusion in patients with acute myocardial infarction. These results suggest a bioactivity response relationship very much like a dose–response relationship in drug trials. (Reinfusion of Enriched Progenitor cells and Infarct Remodeling in Acute Myocardial Infarction [REPAIR-AMI]; NCT00279175 )