Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload.
Limited therapies exist for patients with congenital heart disease (CHD) who develop right ventricular (RV) dysfunction. Bone marrow-derived mesenchymal stem cells (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 = 5) or placebo (n = 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 < 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P < 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P < 0.0001), superior recruitment of endogenous c-kit+ cardiac stem cells to the RV (P < 0.0001) and increased proliferation of cardiomyocytes (P = 0.0009) and endothelial cells (P < 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P = 0.008), increased cardiomyocyte cross-sectional area (P = 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, β-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.
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Brody
B
Wehman
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Sudhish
S
Sharma
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland.
Nicholas
N
Pietris
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Rachana
R
Mishra
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Osama T
OT
Siddiqui
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Grace
G
Bigham
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Tieluo
T
Li
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Emily
E
Aiello
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Sarah
S
Murthi
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Mark
M
Pittenger
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and.
Bartley
B
Griffith
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and skaushal@smail.umaryland.edu.
Sunjay
S
Kaushal
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D018995:Myosin Heavy Chains / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D013552:Swine; D018497:Ventricular Dysfunction, Right / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology
D018994:Myosin Light Chains; D020097:Natriuretic Peptide, Brain; D018995:Myosin Heavy Chains
congenital heart disease; pressure overload; right ventricle; stem cell therapy