Bright Ferritin for Non-Invasive MRI Monitoring of the Fate of Transplanted hPSC-Cardiomyocytes in the Infarcted Rat Heart

Abstract

Purpose: To demonstrate that a recently reported bright ferritin magnetic resonance imaging (MRI) platform can track transplanted human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) longitudinally and on-demand in the rat heart. Methods: Ferritin-overexpressing hPSCs were differentiated into cardiomyocytes and assessed for cell viability, contractile functional proteins, and electrophysiological properties in vitro. In an immunodeficient rat model, hPSC-CMs injected into the left ventricular myocardium were tracked on cardiac MRI at 3 Tesla over 8 weeks in both healthy and infarcted hearts. Longitudinal MRI was accompanied by MnCl2 supplementation for on-demand recall of bright signal from ferritin-overexpressing hPSC-CMs. MRI findings were corroborated against histological validation. Results: Ferritin-overexpressing hPSC-CMs displayed normal morphological and functional phenotypes and created viable grafts in vivo. On-demand recall of bright contrast on MRI was achieved, regardless of interval post-cell transplantation, via MnCl2 administration to precisely map surviving hPSC-CMs in both healthy and infarcted hearts. The spatial distribution of hPSC-CMs on MRI was confirmed throughout the heart by histology. Echocardiography confirmed MnCl2 had no impact on cardiac function, although in vitro tests revealed transiently dampened calcium handling and contractility, an effect from which cells fully recovered after removing MnCl2. Conclusion: Bright ferritin MRI allows longitudinal, non-invasive, and on-demand imaging of the distribution of viable transplanted hPSC-CMs in the healthy and infarcted rat heart.