Background While human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic non-ischemic dilated cardiomyopathy (NIDCM). Objectives The POSEIDON-DCM trial is a randomized comparison of safety and efficacy of autologous (auto) vs. allogeneic (allo) bone marrow-derived hMSCs in NIDCM. Methods Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients (age: 55.8 ± 11.2; 32% female) received hMSCs (100 million) by transendocardial stem cell injection (TESI) in ten left ventricular sites by NOGA Catheter. Treated patients were evaluated at baseline, 30 days, 3-, 6-, and 12-months for safety: serious adverse events (SAE), and efficacy endpoints: Ejection Fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Six Minute Walk Test (6MWT), MACE, and immune-biomarkers. This trial is registered with ClinicalTrials.gov, #NCT01392625. Results There were no 30-day treatment-emergent (TE)-SAEs. 12-month SAE incidence was 28.2% (95% CI: 12.8, 55.1) in allo, and 63.5% (95% CI: 40.8, 85.7; p=0.1004) in auto. One allo-group patient developed an elevated donor specific cPRA. EF increased in allo by 8.0 units (95% Cl: 2.8, 13.2; p=0.004), and in auto: 5.4 units (95% Cl: −1.4, 12.1; p=0.116, allo vs. auto p=0.4887). 6MWT increased for allo: 37.0 meters (95% Cl: 2.0 to 72.0; p=0.04), but not auto: 7.3 meters (95% Cl: −47.8, 33.3; p=0.71, auto vs. allo p=0.0168). MLHFQ score decreased in allo (p=0.0022), and auto (p=0.463; p=0.172). The MACE rate was lower in allo vs. auto (p=0.0186). Tumor necrosis factor alpha (TNF-α) decreased (p=0.0001 for each), to a greater extent in allo vs. auto at six-months (p=0.05). Conclusion These findings demonstrate safety and support greater, clinically meaningful efficacy of allo-hMSC vs. auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results.

Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.

No abstract

BackgroundAging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair.MethodsThis is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion.ResultsNo therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy.ConclusionIntravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder.Clinical Trial Registration www.clinicaltrials.gov: CRATUS (#NCT02065245).

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.

An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. Inconsistent findings have been reported regarding the relationship between the cell dose and clinical benefit. The present study summarizes the data regarding the optimal cell dosage and route of administration from studies of stem cell therapy for heart disease and offers a perspective on future directions.

BackgroundImpaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty.MethodsIn this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively.ResultsThere were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). Overall, the 100-million dose showed the best improvement in all parameters, with the exception of TNF-α, which showed an improvement in both the 100- and 200-million groups (p = .0001 and p = .0001, respectively). The 100-million cell-dose group also showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline.ConclusionsAllo-hMSCs are safe and immunologically tolerated in aging frailty patients. Improvements in functional and immunologic status suggest that ongoing clinical development of cell-based therapy is warranted for frailty.

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.