Multimodal Imaging for In Vivo Evaluation of Induced Pluripotent Stem Cells in a Murine Model of Heart Failure

Myocardial stem cell therapy in heart failure is strongly dependent on successful cellular transfer, engraftment, and survival. Moreover, massive cell loss directly after intramyocardial injection is commonly observed, generating the need for efficient longitudinal monitoring of transplanted cells in order to develop more efficient transplantation techniques. Therefore, the aim of the present study was to assess viability and cardiac retention of induced pluripotent stem cells after intramyocardial delivery using in vivo bioluminescence analysis (BLI) and magnetic resonance imaging (MRI). Murine induced pluripotent stem cells (iPSCs) were transfected for luciferase reporter gene expression and labeled intracellularly with supraparamagnetic iron oxide particles. Consequently, 5 x 10(5) cells were transplanted intramyocardially following left anterior descending coronary artery ligation in mice. Cardiac iPSCs were detected using BLI and serial T2* sequences by MRI in a 14-day follow-up. Additionally, infarct extension and left ventricular (LV) function were assessed by MRI. Controls received the same surgical procedure without cell injection. MRI sequences showed a strong MRI signal of labeled iPSCs correlating with myocardial late enhancement, demonstrating engraftment in the infarcted area. Mean iPSC volumes were 4.2+/-0.4 mm(3) at Day 0; 3.1+/-0.4 mm(3) at Day 7; and 5.1+/-0.8 mm(3) after 2 weeks. Thoracic BLI radiance decreased directly after injection from 1.0 x 10(6) +/- 4.2 x 10(4) (p/s/cm(2)/sr) to 1.0 x 10(5) +/- 4.9 x 10(3) (p/s/cm(2)/sr) on Day 1. Afterward, BLI radiance increased to 1.1 x 10(6) +/- 4.2 x 10(4) (p/s/cm(2)/sr) 2 weeks after injection. Cardiac graft localization was confirmed by ex vivo BLI analysis and histology. Left ventricular ejection fraction was higher in the iPSC group (30.9+/-0.9%) compared to infarct controls (24.0+/-2.1%; P<0.05). The combination of MRI and BLI assesses stem cell fate in vivo, enabling cardiac graft localization with evaluation of LV function in myocardial infarction.