Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Abstract

(MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n ϭ 5) or placebo (n ϭ 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P Ͻ 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P Ͻ 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P Ͻ 0.0001), superior recruitment of endogenous c-kitϩ cardiac stem cells to the RV (P Ͻ 0.0001) and increased proliferation of cardiomyocytes (P ϭ 0.0009) and endothelial cells (P Ͻ 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P ϭ 0.008), increased cardiomyocyte cross-sectional area (P ϭ 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, ␤-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions. stem cell therapy; congenital heart disease; right ventricle; pressure overload CONGENITAL HEART DISEASE (CHD) is the leading cause of morbidity and mortality in children with birth defects. While surgical interventions have dramatically improved outcomes and longevity in patients with CHD, many patients still progress to heart failure, a population that has grown significantly over the last decade (30). In contrast to adult patients, in whom ischemic heart disease is the predominant etiology of heart failure, children with CHD are frequently exposed to acute or chronic ventricular pressure and volume overload, which if untreated can progress to ventricular dysfunction and ultimately to heart failure. Further, patients with CHD who develop right ventricular (RV) dysfunction have the poorest outcomes (23, 26), particularly in those patients with univentricular heart disease i...

Cardiac Progenitor Cells Enhance Neonatal Right Ventricular Function After Pulmonary Artery Banding

“…We previously showed that a different stem cell type, bone marrow-derived mesenchymal stem cells (MSCs), preserved right ventricular (RV) size and function in a neonatal swine model of RV pressure overload at 4 weeks after intramyocardial injection [4]. At the time of this initial study, a contemporaneous cohort of animals underwent RV injection with c-kit þ CPCs but had not yet been analyzed.…”

Persistence and proliferation of human mesenchymal stromal cells in the right ventricular myocardium after intracoronary injection in a large animal model of pulmonary hypertension

“…These investigators found improvement in RV parameters after 30 days; however, they identified relatively few hMSCs retained in the myocardium at day 28 [26]. It is plausible that our findings differ based on the age (neonatal vs. adult) and disease state (none vs. PH with RV remodeling) of the animals studied; the dose of cells administered and route of injection, and the use of immune suppression, which our study did not use.…”

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…In 2011, it was demonstrated that intramyocardially injected BM-derived c-kit + cells stimulate endogenous cardiogenic progenitors without evidence for transdifferentiation or fusion of cells [353]. This was further confirmed in several other studies showing the increase of c-kit + CSC within the heart tissue after MSC transplantation [354,355]. Recently, the injection of BM-derived MNC conditioned media alone was found to significantly increase the number of circulating Sca-1 + and c-kit + cells and favors the infiltration of beneficial endogenous BMderived cells, indicating paracrine signaling as the prevailing mechanism of resident cell recruitment [356].…”

“…The amount of proliferating cardiomyocytes and endothelial cells was significantly elevated after MSC transplantation [354]. As these proliferating cells failed to co-express the active fragment of the Notch 1 receptor N1ICD, the authors concluded that proliferating cells did not arise from endogenous CSCs [354,357].…”