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Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and
Natesh Parashurama1, Byeong-Cheol Ahn1, Keren Ziv1
1From the Department of Radiology, James Clark Center, Molecular Imaging Program at Stanford, 318 Campus Drive West, Room E153, Stanford University, Stanford, CA 94305 (N.P., K.Z., K.I., R.P., J.K.W., D.Y., M.P., Y.F.C., F.H., S.Y., S.S.G.); Department of Cardiovascular Medicine (J.C., F.I., J.K.L., T.T., H.K., C.N.D., M.M., R.D., P.C.Y., T.J.B., P.G.Y., M.V.M.), Department of Cardiothoracic Surgery (J.C.S., D.R.M., J.E.C., A.B.G., R.C.R.), Department of Bioengineering (D.Y., P.G.Y., S.S.G.), Canary Center for Early Detection of Cancer (R.P., S.S.G.), and Department of Materials Science and Engineering (S.S.G.), Stanford University, Stanford, Calif; GE Global Research Center, General Electric, Niskayuna, NY (S.B.); Department of Nuclear Medicine, Kyungpook National University, Daegu, South Korea (B.C.A.); and Advanced Center for Treatment, Research, and Education ACTREC, Tata Memorial Centre, Navi Mumbai, India (P.R.).
Abstract:
Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.
