Abstract 17412: Paracrine Role of B Lymphocytes in Successful Bone Marrow Cell Therapy for Myocardial Infarction

Abstract

Introduction: Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) or cell-free BMC lysate substantially improves post-MI cardiac function in rodent experiments. However, clinical trials of BMC therapy have been less successful. While most mouse experiments use young healthy BMC donors, MI patients undergoing autologous cell therapy (i.e., receiving their own BMCs) are older and are post-MI. We have previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, that donor MI induces inflammation leading to changes in BMC composition, and that BMCs from aged or post-MI mice have reduced levels of B cells, which reportedly can be a therapeutic BMC subpopulation. We recently observed that partial depletion of B cells from young healthy donor BMCs reduces the BMCs’ therapeutic effect, mimicking the effects of donor age or MI. Hypothesis: B cells play a crucial role in BMC therapy for MI, and B cell lysate is also therapeutic. Methods: We induced permanent coronary artery ligation MI, and implanted purified CD19+ bone marrow B cells from young healthy donors into the recipient infarct border zone 3 days post-MI via ultrasound guidance. CD3ε+ T cells and vehicle (HBSS) were injected as negative controls. A similar experiment was carried out with B cell lysate and T cell lysate. Results: In all groups, recipient left ventricular ejection fraction (EF) declined uniformly from baseline to day 2 post-MI, before cell injection. Injection of B cells significantly improved day 28 EF (p<.0005 adjusted for multiple comparisons). In contrast, T cells provided little or no benefit relative to HBSS. Notably, B cell lysate, but not T cell lysate, increased EF comparably to intact B cells. *p<.05 in figure. Conclusions: Bone marrow B cells play a crucial role in BMC therapy for MI via a paracrine mechanism. Reduction of bone marrow B cells by age or MI may explain why autologous BMC therapy in patients has not matched the success of rodent experiments.