Combined reporter gene PET and iron oxide MRI for monitoring survival and localization of transplanted cells in the rat heart.
There is a need for in vivo monitoring of cell engraftment and survival after cardiac cell transplantation therapy. This study assessed the feasibility and usefulness of combined PET and MRI for monitoring cell engraftment and survival after cell transplantation.


METHODS
Human endothelial progenitor cells (HEPCs), derived from CD34+ mononuclear cells of umbilical cord blood, were retrovirally transduced with the sodium iodide symporter (NIS) gene for reporter gene imaging by (124)I-PET and labeled with iron oxides for visualization by MRI. Imaging and histologic analysis were performed on 3 groups of nude rats on days 1, 3, and 7 after intramyocardial injection of 4 million HEPCs.


RESULTS
In vitro studies demonstrated stable expression of functional NIS protein and normal viability of HEPCs after transduction. On day 1, after intramyocardial transplantation, iron- and NIS-labeled HEPCs were visualized successfully on MRI as a regional signal void in the healthy myocardium and on PET as (124)I accumulation. The (124)I uptake decreased on day 3 and was undetectable on day 7, and the MRI signal remained unchanged throughout the follow-up period. Histologic analysis with CD31 and CD68 antibodies confirmed the presence of either labeled or nonlabeled control transplanted HEPCs at the site of injection on day 1 but not on day 7, when only iron-loaded macrophages were seen. Furthermore, deoxyuride-5'-triphosphate biotin nick end labeling showed extensive apoptosis at the site of transplantation.


CONCLUSIONS
The combination of MRI and PET allows imaging of localization and survival of transplanted HEPCs together with morphologic information about the heart. Although iron labeling rapidly loses specificity for cell viability because of phagocytosis of iron particles released from dead cells, reporter gene expression provided specific information on the number of surviving cells. This multimodality approach allows complementary analysis of cell localization and viability.
Higuchi
Takahiro
T
Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Munich, Germany. higuchi@po2.nsknet.or.jp
Anton
Martina
M
Dumler
Katja
K
Seidl
Stefan
S
Pelisek
Jaroslav
J
Saraste
Antti
A
Welling
Andrea
A
Hofmann
Franz
F
Oostendorp
Robert A J
RA
Gansbacher
Bernd
B
Nekolla
Stephan G
SG
Bengel
Frank M
FM
Botnar
Rene M
RM
Schwaiger
Markus
M
D000818:Animals; D002470:Cell Survival; D003287:Contrast Media; D042783:Endothelial Cells / Q000166:cytology* / Q000000981:diagnostic imaging* / Q000502:physiology; D005290:Ferric Compounds; D017930:Genes, Reporter; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000000981:diagnostic imaging* / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D011923:Rats, Nude; D025321:Surgery, Computer-Assisted / Q000379:methods; D027981:Symporters / Q000235:genetics; D000099209:Sodium-Iodide Symporters
D003287:Contrast Media; D005290:Ferric Compounds; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C000499:ferric oxide