Imaging approaches for the study of cell-based cardiac therapies

Abstract

Despite promising preclinical data, the treatment of cardiovascular diseases using embryonic, bone-marrow-derived, and skeletal myoblast stem cells has not yet come to fruition within mainstream clinical practice. Major obstacles in cardiac stem cell investigations include the ability to monitor cell engraftment and survival following implantation within the myocardium. Several cellular imaging modalities, including reporter gene and MRI-based tracking approaches, have emerged that provide the means to identify, localize, and monitor stem cells longitudinally in vivo following implantation. This Review will examine the various cardiac cellular tracking modalities, including the combinatorial use of several probes in multimodality imaging, with a focus on data from the past 5 years.

Figure 1

Embryonic stem cell-derived cardiac precursor cells (ES-CPCs) labeled with SPIOs. Images obtained from the murine heart 1 week after implantation of 500,000 Fe-Pro-labelled ES-CPCs. (a) Full view of the conventional T2*-weighted image. (b) Magnified view of the conventional T2*-weighted image. (c) The corresponding GRASP image. (d) Histology. Abbreviations: GRASP, gradient acquisition for superparamagnetic particles/susceptibility; GRE, gradient-recalled echo. Permission obtained from Wiley © Mani, V. et al. Serial in vivo positive contrast MRI of iron oxide-labeled embryonic stem cell-derived cardiac precursor cells in a mouse model of myocardial infarction. Magn. Reson. Med. 60, 73–81 (2008).

Figure 2

Evaluation of non-infarcted mice. T1-weighted high resolution MRI scan of noninfarcted mouse one day after injection. (a) Longitudinal image indicating position of axial slice (red line) in top frame. (b) Corresponding histology shows GdFM-Cy3 (red) within the myocardial wall (×5 magnification; green indicates cardiac troponin T stain; blue indicates DAPI. (c) Frames 1–10 show different frames within cardiac cycle. *Right ventricle; **Left ventricle. Arrows show volume containing GdFM-Cy3 cells. Abbreviations: DAPI, (4',6- diamidino-2-phenylindole); GdFM-Cy3, gadoflourine M. Permission obtained from the American College of Cardiology Foundation © Adler, E., et al. Derived cardiovascular progenitor cells using Cy3-labeled gadofluorine M in murine myocadium. JACC; Cardiovasc. Imaging 1, 9 (2009).

Figure 3

PET-CT imaging of intramyocardial reporter gene expression. (a) Transverse nonenhanced PET-CT fusion image reconstructed at the level of the LV after administration of transduced human mesenchymal stem cells. The image was acquired 4 h after intravenous FHBG administration. A distinct imaging signal (small arrows) can be delineated at the intramyocardial injection site of human mesenchymal stem cells. Note the postoperative soft-tissue edema, emphysema and fluid collection in the left chest wall (large arrows). (b) Coronal reconstruction of PET data set of the thorax and cranial upper abdomen in the same animal demonstrates high FHBG uptake at the level of intramyocardial injection site (arrows), with low background signal intensity in all other intrathoracic anatomic structures. Note the high tracer accumulation in the liver (white L) due to biliary FHBG excretion. Abbreviations: FHBG, 9-(4-¹⁸F-fluoro-3-hydroxymethylbutyl) guanine; L, left proximal foreleg; LV, left ventricle; R, right proximal foreleg; RV. Permission obtained from the Radiological Society of America © Willmann et al. Imaging gene expression in human mesenchymal stem cells: from small to large animals. Radiology 252, 117–127 (2009).