BACKGROUND Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. We previously showed, using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, that these 2 cell types act synergistically in combination. OBJECTIVES To more accurately model the clinical situation, we tested whether the combination of autologous MSCs and CSCs produced greater improvement of cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. METHODS Three months after ischemia/reperfusion infusion injury, Gottingen mini-swine were injected transendocardially with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), MSCs, or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed by cardiac magnetic resonance at baseline and before and after therapy. RESULTS Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs: −44.1 ± 6.8%; CSC/MSC: −37.2 ± 5.4%; placebo: −12 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs: +2.9 ± 1.6; CSC/MSC: +6.9 ± 2.8; placebo: +2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain, but only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. CONCLUSIONS These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

Background The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). Objective We tested the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. Methods Gottingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of either allo-MSC + allo-CSC (ACCT: 200 million MSCs/1 million CSCs, n=7), 200 million allo-MSC (n=8), 1 million allo-CSC (n=4), or placebo (Plasma-Lyte A, n=6)]. Swine were assessed by cardiac magnetic resonance imaging (cMR) and pressure volume catheterization. Immune response was tested by histological analyses. Results Both ACCT and allo-MSCs reduced scar size by −11.1±4.8%, (p=0.012) and −9.5±4.8 (p=0.047), respectively. Only ACCT, but not MSC or CSC, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure volume relation (+0.98±0.41 mmHg/mL, p=0.016) The ACCT group had more phospho-histone H3 (pHH3)+ (a marker of mitosis) cardiomyocytes (p=0.04), and non-cardiomyocytes (p=0.0002) compared to the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC swine contained immunotolerant CD3+/CD25+/FoxP3 regulatory T cells (p<0.0001). Histologic analysis showed absent to low grade inflammatory infiltrates without cardiomyocyte necrosis. Conclusion ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunological reaction. Clinical translation to humans is warranted.

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Rationale Transendocardial Stem Cell Injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the impact of the injection site remains unknown. Objective To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in non-injected segments. Methods and Results Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13-months after TESI. Segmental early enhancement defect (SEED, a measure of scar size) was reduced by TESI in both injected (−43.7±4.4%, n=95, p<0.01) and non-injected segments (−25.1±7.8%, n=148, p<0.001; between group comparison p<0.05). Conversely, segmental ejection fraction (SEF, a measure of contractility) improved in injected scar segments (19.9±3.3 to 26.3±3.5%, p=0.003) but not in non-injected scar segments (21.3±2.6 to 23.5±3.2%, p=0.20, between group comparison p<0.05). In the subgroup of scar segments with baseline SEF<20%, the SEF improvement was even greater in injected segments (12.1±1.2% to 19.9±2.7%, n=18, p=0.003) vs. non-injected segments (13.3±1.3% to 16.1±2.1%, n=15, p=0.05; between group comparison p<0.05). Conclusions These findings illustrate a dichotomy in regional responses to TESI. Although scar reduction was evident at the site of TESI and remotely, ventricular functional responses occurred preferentially at the sites of TESI. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Cell-based treatment represents a new generation in the evolution of biological therapeutics. A prototypic cell-based therapy, the mesenchymal stem cell (MSC), has successfully entered phase III pivotal trials for heart failure, signifying adequate enabling safety and efficacy data from phase I and II trials. Successful phase III trials can lead to approval of a new biologic therapy for regenerative medicine. The use of stem or progenitor cells therapeutically is under investigation for the treatment of chronic diseases, including cardiovascular pathologies.1 Not unusual for an early stage disruptive technology, early findings have led the field to an important and controversial cross-roads. Based in large part on disagreements surrounding mechanism of action of cell-based therapy, some authors have called for a reappraisal of the existing data, while others have concluded that the field has “evolved too quickly into clinical practice” and that we “need to go back to the bench”.2 However, there are many historical examples including the notable examples of aspirin and opioids that were employed therapeutically before the mechanisms of actions were fully understood. In the midst of this debate regarding mechanism of action of cell therapy, an emerging field of investigation that holds great promise needs to be highlighted. In this context, the development of MSCs has followed the characteristic trajectory of preclinical and clinical development, supported by data highly predictive of successful therapeutic outcome. Most importantly, because of its allogeneic potential, MSCs can be viewed as a true cellular biological therapy with the capacity for high volume quality-controlled production and “off the shelf” usage.3