Abstract 2716: High-Mobility Group Box 1 Protein (HMGB1) Released by Cell Transplantation Plays an Important Role in the Therapeutic Effects for Treating Chronic Ischemic Heart Failure
Background: It has been shown that transplantation of bone marrow (BM) cells improves cardiac function post myocardial infarction, but the mechanism responsible remains unknown. The ability of BM cells to survive in the myocardium and to differentiate into cardiac phenotype is limited, suggesting an alternative pathway. HMGB1 is an abundant chromatin protein that is passively released by necrotic cells and secreted by inflammatory cells to modulate inflammatiory response and tissue repair process. We hypothesized that the HMGB1 released from dead grafted BM cells and subsequent modification of inflammatory process might play an important role in the improvement of cardiac function after BM transplantation.
Methods and Results: Three weeks after left coronary artery ligation of rat hearts, ten million GFP+ BM mononuclear cells were implanted into the border zone by direct intramuscular injection. To inhibit the effects of HMGB1, 50μg of anti-HMGB1 antibody (clone FBH7) or control IgG was added to donor cell suspension. After 4 weeks, improvement in LVEF observed in the control antibody-treated group (43.1±2.7% from 36.9±1.7% pre cell transplantation, n=5) was markedly diminished by inhibiting HMGB1 (30.4±1.2%, n=6, p<0.05). Real time PCR analysis of the infarct/border zone myocardium demonstrated that the expression profile of cytokines and growth factors, which are believed to be important in the paracrine effect of BM cell transplantation, was modulated by the inhibition of HMGB1 (Table⇓). Immunohistochemistry demonstrated that the myocardial accumulation of CD45+ inflammatory cells after BM cell transplantation was increased by inhibiting HMGB1.
Conclusion: HMGB1 plays an important role in the improvement of cardiac function after intramyocardial BM cell transplantation in post-infarction chronic heart failure. Modifying the effects of HMGB1 in cell transplantation might be a useful strategy for cardiac regenerative therapy.