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Combined Reporter Gene PET and Iron Oxide MRI for Monitoring Survival and Localization of Transplanted Cells in the Rat Heart

¹ Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Munich, Germany; ² Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Munich, Germany; ³ Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Munich, Germany; ⁴ Abteilung für Gefässchirurgie, Technische Universität München, Munich, Germany; ⁵ Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany; and ⁶ III. Medizinische Klinik und Poliklinik Klinikum rechts der Isar, Technische Universität München, Munich, Germany

View larger version (14K): [in this window] [in a new window]   FIGURE 1.  (A) Increased 99mTc-uptake was demonstrated after retroviral NIS gene transduction. (B) 99mTc-uptake correlated well with percentage of NIS-positive cells as determined by FACS analysis. (C) Results of electrophysiologic characterization. Current was recorded from control HEPCs (control a), uninfected HEPCs derived from transduced pool (control b), or hNIS-expressing HEPC (NIS). Graph shows no difference in current-voltage relationships between control and NIS cells at baseline. (D) Cells were perfused with I– in bathing solution at indicated concentrations. Representative currents from uninfected cells (control HEPC) and NIS-positive cells (NIS labeled) are shown. Current was recorded at Vh = –50 mV. Superfusion of I– induced inward current only in NIS-expressing HEPC, indicating functionality of NIS protein.

View larger version (38K): [in this window] [in a new window]   FIGURE 2.  (A) Representative MR and PET images of rat thorax 1 d after cell transplantation. Donor cells were labeled with iron (left), NIS only (middle), or both iron and NIS (right). T2*-weighted MR images are shown in top row, 124I-PET images in middle row, and fused images with 13N-NH3 (gray scale) and 124I (color scale) in bottom row. Rat with iron-labeled HEPCs showed signal void at myocardium by MRI, whereas rat with HEPCs expressing NIS demonstrated focal 124I accumulation by PET. (B) Examples of consecutive myocardial sections of rat heart on day 1 after transplantation of HEPCs labeled with iron oxides, NIS reporter, and LacZ reporter. Autoradiography for 124I uptake mediated by NIS reporter (left), X-galactosidase staining for LacZ gene expression of graft cells (middle), and Prussian blue staining for iron particle detection (right) are seen in corresponding locations. (C) Mean (±SD) time–activity curves after 124I administration of transplanted cell and left ventricular blood measured by PET (n = 4).

View larger version (28K): [in this window] [in a new window]   FIGURE 3.  (A) Results from longitudinal imaging of transplanted HEPCs labeled with both iron oxides and NIS gene. Representative short-axis images of rat on days 1, 3, and 7 after transplantation. (B) Time course of mean (±SD) MRI and PET signal. Contrast-to-noise ratio by MRI at site of cell injection was stable over 7 d, but 124I uptake decreased rapidly and was not detectable on day 7 after cell engraftment (*P < 0.001). (C and D) Results of autoradiography confirmed changes in 124I signal by PET. Representative autoradiograph (C) and bar graph of mean (±SD) 124I uptake ratio (D) demonstrate rapid decrease of uptake signal as early as 3 d after transplantation (*P < 0.001).

View larger version (149K): [in this window] [in a new window]   FIGURE 4.  Histologic detection of iron particles after transplantation of iron-labeled HEPCs in rat hearts. Representative images of human CD31 immunohistochemical analysis for detection of graft HEPCs on days 1 (A) and 7 (B), Prussian-blue iron staining on days 1 (C) and 7 (D), and CD68 immunohistochemical macrophage analysis on days 1 (E) and 7 (F) are shown. Localization of iron particles and graft HEPCs was observed on day 1 at site of cell transplantation (A and C). However, iron particles remained in heart on day 7, despite absence of graft HEPCs (B and D). On day 7, increased number of macrophages (F) was found.