TY - JOUR
T1 - Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload
AU - Wehman, Brody
AU - Sharma, Sudhish
AU - Pietris, Nicholas
AU - Mishra, Rachana
AU - Siddiqui, Osama T.
AU - Bigham, Grace
AU - Li, Tieluo
AU - Aiello, Emily
AU - Murthi, Sarah
AU - Pittenger, Mark
AU - Griffith, Bartley
AU - Kaushal, Sunjay
N1 - Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/6
Y1 - 2016/6
N2 - 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.
AB - 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.
KW - Congenital heart disease
KW - Pressure overload
KW - Right ventricle
KW - Stem cell therapy
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U2 - 10.1152/ajpheart.00955.2015
DO - 10.1152/ajpheart.00955.2015
M3 - Article
C2 - 27106046
AN - SCOPUS:84983789342
SN - 0363-6135
VL - 310
SP - H1816-H1826
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 11
ER -