Stem Cells Transl Med. 2016 Aug;5(8):1004-13. doi: 10.5966/sctm.2015-0298. Epub 2016 Jun 22.

Human Umbilical Cord-Derived Mesenchymal Stromal Cells Improve Left Ventricular Function, Perfusion, and Remodeling in a Porcine Model of Chronic Myocardial Ischemia.

Liu CB¹, Huang H², Sun P³, Ma SZ³, Liu AH¹, Xue J¹, Fu JH¹, Liang YQ³, Liu B⁴, Wu DY³, Lü SH⁵, Zhang XZ⁵.

Author information

¹Department of Cardiovascular Medicine, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China.

²Department of Anesthesia, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China.

³Ivy Institute of Stem Cells Company Limited, Beijing, People’s Republic of China.

⁴307-Ivy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China.

⁵Department of Cardiovascular Medicine, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China

Abstract

Stem cell therapy has emerged as a new strategy for treatment of ischemic heart disease. Although umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have been used preferentially in the acute ischemia model, data for the chronic ischemia model are lacking. In this study, we investigated the effect of UC-MSCs originated from Wharton’s jelly in the treatment of chronic myocardial ischemia in a porcine model induced by ameroid constrictor. Four weeks after ameroid constrictor placement, the surviving animals were divided randomly into two groups to undergo saline injection (n = 6) or UC-MSC transplantation (n = 6) through the left main coronary artery. Two additional intravenous administrations of UC-MSCs were performed in the following 2 weeks to enhance therapeutic effect. Cardiac function and perfusion were examined just before and at 4 weeks after intracoronary transplantation. The results showed that pigs with UC-MSC transplantation exhibited significantly greater left ventricular ejection fraction compared with control animals (61.3% ± 1.3% vs. 50.3% ± 2.0%, p < .05). The systolic thickening fraction in the infarcted left ventricular wall was also improved (41.2% ± 3.3% vs. 46.2% ± 2.3%, p < .01). Additionally, the administration of UC-MSCs promoted collateral development and myocardial perfusion. The indices of fibrosis and apoptosis were also significantly reduced. Immunofluorescence staining showed clusters of CM-DiI-labeled cells in the border zone, some of which expressed von Willebrand factor. These results suggest that UC-MSC treatment improves left ventricular function, perfusion, and remodeling in a porcine model with chronic myocardial ischemia.

SIGNIFICANCE:

Ischemic heart disease is the leading cause of death worldwide. Many patients with chronic myocardial ischemia are not suitable for surgery and have no effective drug treatment; they are called “no-option” patients. This study finds that umbilical cord-derived mesenchymal stromal cells transplanted by intracoronary delivery combined with two intravenous administrations was safe and could significantly improve left ventricular function, perfusion, and remodeling in a large-animal model of chronic myocardial ischemia, which provides a new choice for the no-option patients. In addition, this study used clinical-grade mesenchymal stem cells with delivery and assessment methods commonly used clinically to facilitate further clinical transformation.

KEYWORDS: Chronic myocardial ischemia; Ischemic heart disease; Mesenchymal stromal cells; Umbilical cord; Ventricular remodeling

Basic Res Cardiol. 2008 Nov;103(6):525-36. doi: 10.1007/s00395-008-0741-0. Epub 2008 Aug 14.

Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricularfunction in a porcine model of myocardial infarction.

Halkos ME¹, Zhao ZQ, Kerendi F, Wang NP, Jiang R, Schmarkey LS, Martin BJ, Quyyumi AA, Few WL, Kin H, Guyton RA, Vinten-Johansen J.

Author information

¹Cardiothoracic Research Laboratory, Division of Cardiothoracic Surgery, Emory Crawford Long Hospital, 550 Peachtree Street, NE, Atlanta, GA 30308, USA.

Abstract

Transplantation of stem cells may improve regional perfusion and post-infarct ventricular function, but the optimal dose and efficacy of cell delivery via the intravenous route has not been determined. This study tested the hypothesis that intravenous infusion of bone marrow-derivedmesenchymal stem cells (MSCs) enhances regional perfusion and improves ventricular function after myocardial infarction. In a closed-chest pigmodel, the LAD coronary artery was occluded for 75 min by angioplasty balloon inflation followed by 12 weeks of reperfusion. After 15 min of reperfusion, pigs randomly received 1 of 4 treatments: (1) Vehicle (Control, n = 10); (2) 1 x 10(6) MSCs/kg (1 mill, n = 7); (3) 3 x 10(6) MSCs/kg (3 mill, n = 8) and (4) 10 x 10(6) MSCs/kg (10 mill, n = 8). Angiogenesis was demonstrated by immunohistochemical staining, myocardial blood flow (steady state and vasodilator reserve) was measured using 15 microm neutron-activated microspheres, and cardiac function was determined by contrast left ventriculography (ejection fraction) and pressure-volume relationships. After 12 week of reperfusion, von Willebrand Factor-positive vessels and tissue vascular endothelial growth factor (VEGF) expression in the scar zone was significantly greater in all MSCs-treated animals relative to Control. Steady state myocardial blood flow in the scar tissue was comparable among groups. However, adenosine recruited vasodilator reserve in the scar zone induced by intracoronary adenosine was significantly higher in the MSC-treated animals compared to Control. Furthermore, preload-recruitable stroke work and systolic performance were significantly greater compared to Control. In conclusion, these data demonstrate that intravenous delivery of MSCs during early reperfusion augments vasculogenesis, enhances regional perfusion, and improvespost-infarct ventricular function. The results suggest that intravenous infusion of MSCs is an effective modality for the treatment of ischemia/reperfusion induced myocardial injury.

Keywords: angiogenesis, cardiac function, myocardial infarction, mesenchymal stem cells, reperfusion

Int J Cardiol. 2013 Dec 10;170(2):246-51. doi: 10.1016/j.ijcard.2013.10.079. Epub 2013 Oct 28.

Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina–final 3-year follow-up.

Mathiasen AB¹, Haack-Sørensen M, Jørgensen E, Kastrup J.

Author information

¹Cardiac Stem Cell Laboratory, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Abstract

BACKGROUND: The study assessed long-term safety and efficacy of intramyocardial injection of autologous bone-marrow derived mesenchymal stromal cells (BMMSCs) in patients with severe stable coronary artery disease (CAD) and refractory angina.

METHODS: Thirty-one patients with severe stable CAD and refractory angina were included. Patients had reversible myocardial ischemia and no further revascularization options. Autologous BMMSCs were isolated, culture expanded and stimulated with vascular endothelial growth-factor to facilitate endothelial differentiation. BMMSCs were injected into an ischemic, viable region of the myocardium. Patients were followed for 3 years.

RESULTS: We found significant clinical improvements in exercise time (p=0.0016), angina class (CCS) (p<0.0001), weekly number of angina attacks (p<0.0001) and use of nitroglycerine from (p=0.0017). In the Seattle Angina Questionnaire there were significant improvements in physical limitation score, angina stability score, angina frequency score and quality of life score (all p<0.0001). When comparing all hospital admissions from 3 years before to 3 years after treatment, we observed highly reduced admission rates for stable angina (p<0.0001), revascularization (p=0.003) and overall cardiovascular disease (p<0.0001). No early or late side-effects of the treatment were observed.

CONCLUSIONS: The final 3-year follow-up data after intramyocardial injection of autologous BMMSCs, in patients with severe CAD and refractory angina, demonstrated sustained clinical effects, reduced hospital admissions for cardiovascular disease and excellent long-term safety. The results indicate that autotransplantation of BMMSCs to the heart does not only improve symptoms but also slows down disease progression. TRIAL REGISTRATION: ClinicalTrials.gov NCT00260338.

KEYWORDS: Angiogenesis; Chronic myocardial ischemia; Mesenchymal stromal cell; Refractory angina; Stem cell; Stem cell therapy