Intracoronary Administration of Allogeneic Adipose Tissue–Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction

Abstract

BackgroundAutologous adipose tissue–derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post–myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long‐term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance.Methods and ResultsThirty‐eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow‐ups were performed at short (2 days after acute myocardial infarction vehicle‐treated, n=10; ATMSCs‐treated, n=9) or long term (60 days after acute myocardial infarction vehicle‐treated, n=7; ATMSCs‐treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs‐treated animals (48.6±6% versus 55.9±5.7% in vehicle; P=0.017); enhancement of the reparative process with up‐regulated vascular endothelial growth factor, granulocyte macrophage colony‐stimulating factor, and stromal‐derived factor‐1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle; P=0.016). In long‐term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day‐7 and day‐60 cardiac magnetic resonance studies in ATMSCs‐treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days; P=0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days; P=0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs‐treated animals (118±18 versus 92.4±24.3 vessels/mm2 in vehicle; P=0.045). Cardiac magnetic resonance–measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point.ConclusionsIn this porcine acute myocardial infarction model, allogeneic ATMSCs‐based therapy was associated with increased cardioprotective and reparative mechanisms and with better cardiac magnetic resonance–measured perfusion. No effect on left ventricular volumes or ejection fraction was observed.

Adipose-Derived Stromal/Stem Cells from Large Animal Models: from Basic to Applied Science

“…ASCs are routinely characterized using a panel of surface markers or occasionally pluripotency-associated markers, including Oct4, Nanog, and Sox2, which have been shown to be expressed in pig ASCs [21,30,61,62]. Despite any differences in species or fat depot, the immunophenotype of ASCs is uniformly consistent between laboratories [62][63][64][65]. Indeed, according to the current literature, markers that show strong positive expression on livestock ASCs are CD29, CD44, CD73, CD90, and CD105, whereas CD11b, CD14, CD34, CD45, and HLA-DR demonstrate low or lacking expression [62][63][64][65].…”

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

“…MSCs from alternative sources [23]. Among all transplantable seed cells, ADMSCs have the advantages of easy sampling, multi-directional differentiation potential, with few ethical problems, rapid proliferation in vitro and low immunogenicity [2].…”

“…These therapies utilizating stem cell to regenerate lost cardiac muscle are clinically attractive. The cardioprotective effects observed with cell therapy involving MSCs, pluripotent stem cells derived from mesoderm, may be in large part secondary to secreted paracrine factors that enhance endogenous reparative pathways rather than the generation of new cardiac tissue [2,3]. The results from clinical and preclinical studies have been variable and the effect of MSCs transplantation have been shown to be limited, with generally modest benefits in human trials and disappointingly low levels of cell persistence and cardiomyocyte differentiation [4,5].…”

Plasticity of Adipose Tissue-Derived Stem Cells and Regulation of Angiogenesis

“…However, it is too early to conclude on promising results in preclinical animal studies or clinical trials for myocardial infarction ( Lee H.W. et al, 2015 ; Kim et al, 2016 ; Bobi et al, 2017 ; Joo et al, 2017 ), ischemic cardiomyopathy ( Suzuki et al, 2015 ), stroke ( Gutiérrez-Fernández et al, 2013 ; Grudzenski et al, 2017 ), and Alzheimer’s disease ( Lee et al, 2018 ). In light of these introductory remarks, it is apparent that deciphering the novel regulatory mechanisms of the self-renewal and differentiation of ASCs would promote application of advanced and safe protocols for regenerating therapy.…”