Pluripotent stem cells derived cardiac progenitors cells graft improve right ventricular function in a porcine model of repaired Tetralogy of Fallot

Introduction Adult individuals with a cardiac congenital disease are emerging as a major patient population in hospitals. Right ventricular (RV) failure with limited pharmacological therapeutic approaches is often the cause of premature death and morbidity. Objective Cell therapy turns out to be an alternative approach in order to regenerate the RV and/or to improve mechanical function through other biological mechanisms. Method We used an immune-suppressed porcine model of repaired Tetralogy of Fallot that features within 5 months a RV pressure and volume overload leading to a defect in its mechanical function. Pluripotent stem cells derived cardiac progenitors were seeded in a collagen/alginate/gelatin hydrogel (stiffness as low as 1 kPa) printed and polymerized on a collagen membrane patch with the size of the pig's RV. The elastic patch was then grafted on the surface of the pig's epicardium without any suture. Myocardial function was assessed by echocardiography using standard (TAPSE, s’wave, FAC) and strain parameters before and after cell therapy. Pigs were euthanized 2 months post-graft, the heart explanted and the RV used for histology and immunostaining to track the fate of human cells. Results After cell therapy, RV dilatation decreased, overall RV function and RV myocardial contractility were improved on echocardiography. A significant number of human cardiac progenitors were found in the patch and within the myocardium in fibrotic interstitial space. Cells were still differentiating after 2 months post-graft while others were differentiated as assessed by the presence of sarcomeric actinin. Markers of cell proliferation and senescence were further used to better characterize the origin of the RV function improvement. Conclusion Cell therapy of RV failure could thus be a therapeutic option for adults cardiac congenital patients.