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PRE-CLINICAL RESEARCH

Ectopic Expression of the Sodium-Iodide Symporter Enables Imaging of Transplanted Cardiac Stem Cells In Vivo by Single-Photon Emission Computed Tomography or Positron Emission Tomography

John Terrovitis, MD^_*, Keng Fai Kwok, BS, Riikka Lautamäki, MD, PhD, James M. Engles, MS, MBA, Andreas S. Barth, MD, PhD^_*, Eddy Kizana, MBBS, PhD^_*, Junichiro Miake, MD, PhD^_*, Michelle K. Leppo, BS^_*, James Fox, BS, Jurgen Seidel, PhD, Martin Pomper, MD, PhD, Richard L. Wahl, MD, Benjamin Tsui, PhD, Frank Bengel, MD, Eduardo Marbán, MD, PhD^_* and M. Roselle Abraham, MD^_*,_*

^_* Department of Cardiology, Johns Hopkins University, Baltimore, Maryland
Department of Diagnostic Imaging Physics, Johns Hopkins University, Baltimore, Maryland
Department of Nuclear Medicine, Johns Hopkins University, Baltimore, Maryland
Department of Radiology, Johns Hopkins University, Baltimore, Maryland

Manuscript received February 26, 2008; revised manuscript received May 7, 2008, accepted June 19, 2008.

^_* Reprint requests and correspondence: Dr. M. Roselle Abraham, Department of Medicine, 720 Rutland Avenue, Ross 844, Baltimore, Maryland 21205 (Email: mabraha3{at}jhmi.edu).

Objectives: We examined the sodium-iodide symporter (NIS), which promotes in vivo cellular uptake of technetium 99m (^99mTc) or iodine 124 (¹²⁴I), as a reporter gene for cell tracking by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging.

Background: Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo.

Methods: The human NIS complementary deoxyribonucleic acid was transduced into rat cardiac-derived stem cells (rCDCs) using lentiviral vectors. Rats were injected intramyocardially with up to 4 million NIS⁺-rCDCs immediately after left anterior descending coronary artery ligation. Dual isotope SPECT (or PET) imaging was performed, using ^99mTc (or ¹²⁴I) for cell detection and thallium 201 (or ammonia 13) for myocardial delineation. In a subset of animals, high resolution ex vivo SPECT scans of explanted hearts were obtained to confirm that in vivo signals were derived from the cell injection site.

Results: NIS expression in rCDCs did not affect cell viability and proliferation. NIS activity was verified in isolated transduced cells by measuring ^99mTc uptake. NIS⁺ rCDCs were visualized in vivo as regions of ^99mTc or ¹²⁴I uptake within a perfusion deficit in the SPECT and PET images, respectively. Cells could be visualized by SPECT up to 6 days post-injection. Ex vivo SPECT confirmed that in vivo ^99mTc signals were localized to the cell injection sites.

Conclusions: Ectopic NIS expression allows noninvasive in vivo stem cell tracking in the myocardium, using either SPECT or PET. The general approach shows significant promise in tracking the fate of transplanted cells participating in cardiac regeneration, given its ability to observe living cells using clinically applicable imaging modalities.

Key Words: stem cells • imaging • SPECT • PET

Abbreviations and Acronyms   CDC = cardiac-derived stem cell   CMV = cytomegalovirus promoter   CR = contrast ratio   CT = computed tomography   LV = left ventricle/ventricular   MRI = magnetic resonance imaging   NIS = sodium-iodide symporter   PET = positron emission tomography   rCDC = rat cardiac-derived stem cell   RT-PCR = reverse transcription-polymerase chain reaction   SPECT = single-photon emission computed tomography

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