Background-Cardiac cell therapy for older patients who experience a myocardial infarction may require highly regenerative cells from young, healthy (allogeneic) donors. Bone marrow mesenchymal stem cells (MSCs) are currently under clinical investigation because they can induce cardiac repair and may also be immunoprivileged (suitable for allogeneic applications). However, it is unclear whether allogeneic MSCs retain their immunoprivilege or functional efficacy late after myocardial implantation. We evaluated the effects of MSC differentiation on the immune characteristics of cells in vitro and in vivo and monitored cardiac function for 6 months after post-myocardial infarction MSC therapy. Methods and Results-In the in vitro experiments, inducing MSCs to acquire myogenic, endothelial, or smooth muscle characteristics (via 5-azacytidine or cytokine treatment) increased major histocompatibility complex-Ia and -II (immunogenic) expression and reduced major histocompatibility complex-Ib (immunosuppressive) expression, in association with increased cytotoxicity in coculture with allogeneic leukocytes. In the in vivo experiments, we implanted allogeneic or syngeneic MSCs into infarcted rat myocardia. We measured cell differentiation and survival (immunohistochemistry, real-time polymerase chain reaction) and cardiac function (echocardiography, pressure-volume catheter) for 6 months. MSCs (versus media) significantly improved ventricular function for at least 3 months after implantation. Allogeneic (but not syngeneic) cells were eliminated from the heart by 5 weeks after implantation, and their functional benefits were lost within 5 months. Conclusions-The long-term ability of allogeneic MSCs to preserve function in the infarcted heart is limited by a biphasic immune response whereby they transition from an immunoprivileged to an immunogenic state after differentiation, which is associated with an alteration in major histocompatibility complex-immune antigen profile. (Circulation. 2010; 122:2419-2429.)Key Words: stem cells Ⅲ immune system Ⅲ myocardial infarction Ⅲ transplantation B one marrow mesenchymal stem cells (MSCs) have been widely investigated for their potential to prevent cardiac dysfunction after a myocardial infarction (MI). In preclinical studies conducted with young animals, implanted MSCs effectively restored ventricular function after acute or chronic MI. 1,2 The early clinical trials with aging patients demonstrated statistically significant, but comparatively limited, beneficial effects on ventricular volumes and ejection fraction when the patients received autologous MSCs. 3 This muted response was due largely to an age-related decrease in the regenerative capacity of the patients' cells, as demonstrated in studies that examined age-related changes in autologous progenitor cells. 4,5 A source of highly regenerative donor cells would thus dramatically advance the prevention of congestive heart failure in aged patients who have multiple comorbidities. Clinical Perspective on p 2429Allogeneic MSCs is...

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C oronary heart disease is the leading cause of the rising incidence of heart failure worldwide.1 Following myocardial infarction (MI), the limited regenerative potential of the heart causes scar formation in and around the infarction, leading to abnormal electric signal propagation and desynchronized cardiac activation and contraction.2 The lack of electric connection between healthy myocardium and the scar with its islands of intact cardiomyocytes contributes to progressive functional decompensation. Injectable biomaterial has shown promise as an alternative biological treatment option after MI to reduce adverse remodeling and preserve cardiac function.3,4 Among their many advantages, injectable materials can be delivered alone or as a vehicle carrying combination therapies, including cells or growth factors, and may provide mechanical and functional support to the injured heart. Over the past decade, several injectable biomaterials such as collagen, 5,6 alginate, 7 and fibrin 8 have been extensively studied. Organic polymers that conduct electricity (conductive polymers) were first described in 1977, and this discovery was awarded the Nobel prize in 2000.9,10 Conductive polymers are particularly appealing because they exhibit electric properties similar to metals and semiconductors while retaining flexibility, ease of processing, and modifiable conductivity. The electric properties of these materials can be fine-tuned by altering their synthetic processes, including the addition of specific chemical agents.11 Biological applications of conductive polymersBackground-Efficient cardiac function requires synchronous ventricular contraction. After myocardial infarction, the nonconductive nature of scar tissue contributes to ventricular dysfunction by electrically uncoupling viable cardiomyocytes in the infarct region. Injection of a conductive biomaterial polymer that restores impulse propagation could synchronize contraction and restore ventricular function by electrically connecting isolated cardiomyocytes to intact tissue, allowing them to contribute to global heart function. Methods and Results-We created a conductive polymer by grafting pyrrole to the clinically tested biomaterial chitosan to create a polypyrrole (PPy)-chitosan hydrogel. Cyclic voltammetry showed that PPy-chitosan had semiconductive properties lacking in chitosan alone. PPy-chitosan did not reduce cell attachment, metabolism, or proliferation in vitro. Neonatal rat cardiomyocytes plated on PPy-chitosan showed enhanced Ca 2+ signal conduction in comparison with chitosan alone. PPy-chitosan plating also improved electric coupling between skeletal muscles placed 25 mm apart in comparison with chitosan alone, demonstrating that PPy-chitosan can electrically connect contracting cells at a distance. In rats, injection of PPy-chitosan 1 week after myocardial infarction decreased the QRS interval and increased the transverse activation velocity in comparison with saline or chitosan, suggesting improved electric conduction. Optical mapping showed incr...

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