Abstract 11250: Bone Marrow Mononuclear Cell Transplantation Improves Cardiac Function in Ischemic Cardiomyopathy via High Mobility Group Box 1 Released from Dead Donor Cells
Injection of bone marrow mononuclear cells (BMCs) improves cardiac function in ischemic cardiomyopathy allegedly due to the “paracrine effect” mediated by secretion from surviving BMCs. However, donor cell survival is extremely poor; the majority of injected cells are dead shortly after injection, raising a doubt to this concept. High mobility group box 1 (HMGB1) was originally identified as a nuclear protein stabilizing nucleosomes, and is also released from damaged cells to act as a damage associated molecular pattern molecule. We have previously reported that administration of HMGB1 improves the cardiac function in ischemic cardiomyopathy. We thus hypothesized that HMGB1 released from dead donor cells may contribute to the therapeutic effect of BMC injection.
Methods & Results: Ten million syngeneic BMCs or PBS only (control) were intramyocardially injected 4 weeks after coronary artery occlusion in rats. At one hour after BMC injection, HMGB1 level in peripheral blood was elevated compared to the control (16.2±2.5 vs 6.3±1.0 ng/ml). In additional groups, BMCs were injected together with 50μ g of anti-HMGB1 neutralizing antibody or isotype-matched IgG (n=6-10 in each group). Four weeks after BMC injection, echocardiography and catheterization showed improvement of cardiac function compared to the control (% fractional shortening; 31.5±1.2 vs 28.5±1.6%). Of note, this effect was abolished by HMGB1 inhibition (26.4±1.0%) but not by IgG injection (30.9±1.2%). This benefit from BMC injection was associated with reduced fibrosis, improved neovascular formation, attenuated accumulation of CD45+ inflammatory cells, and increased proliferative activity, while all these beneficial changes were eliminated by HMGB1 inhibition. Interestingly, BMC injection two-fold increased CD163+ M2 (alternatively activated; tissue healing) macrophages, but not CD86+ M1 (classically activated; pro-inflammatory) macrophages, compared to the control, whereas HMGB1 inhibition abolished such macrophage polarization towards tissue recovery.
Conclusion: HMGB1 was released from dead donor cells after BMC injection, and played an important role in the therapeutic effect for ischemic cardiomyopathy, including an increase in M2 macrophage polarization.
- © 2012 by American Heart Association, Inc.