Abstract 4296: Allogeneic Bone Marrow Mesenchymal Cells Improved Heart Function but Were Rejected after Myogenic Differentiation

Abstract

Rationale: Allogeneic bone marrow mesenchymal stem cells (MSC) are currently undergoing clinical trials to test their potential to repair the heart after a myocardial infarction (MI). MSCs can improve function, but neither the host immune responses nor the fate of these cells has been extensively investigated. This study compared the outcomes of allogeneic and syngeneic MSC transplantation after an MI. Methods: Female Lewis rat underwent coronary ligation. Three weeks later, allogeneic or syngeneic MSCs (3×10 6 /rat) from male rats (Wister or Lewis, respectively) were implanted into the infracted region. We evaluated implanted cell survival (real-time PCR to quantify Y-chromosomes), cytokines (RT-PCR) and infiltrating cells (immunostaining) in the heart, and allogeneic antibodies in the blood. Cardiac function was assessed by echocardiography and pressure-volume catheters. Immune antigen expression (RT-PCR, immunostaining and flow cytometry) was characterized in the MSCs before and after myogenic differentiation. Results: At 1 week post implantation, cell survival was similar in the allogeneic and syngeneic groups. Gene expression of 11 cytokines and T-cell infiltration into the cell-implanted region were also similar, but more B-cells were observed in the allogeneic group (p<0.05 vs. syngeneic group). Allo-antibodies (IgG1) against Wistar MSCs were detected in the peripheral blood of animals that received allogeneic cells. At 5 weeks after delivery, implanted MSCs were detected only in the syngeneic group. Cardiac function was equally restored in both cell groups (ejection fraction: allogeneic=30.4±1.8%; syngeneic=29.5±2.8%; p<0.05 vs. media controls; control=24.8±3.2%); these data were supported by the pressure-volume analysis. Myogenic differentiation (expression of Nkx2.5, MyoD, MHCβ), CD86 expression and MHC class II molecules were observed in the MSCs after prolonged culture, which could explain why the cells were rejected. Conclusions: Allogeneic BMSC transplantation produced a robust cardiac functional improvement, but following myogenic differentiation the cells were no longer immunoprivileged. Rejection of the allogeneic cells could limit their long term benefit on cardiac remodeling after an MI.