Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis.
AC133 cells, a subpopulation of CD34+ hematopoietic stem cells, can transform into endothelial cells that may integrate into the neovasculature of tumors or ischemic tissue. Most current imaging modalities do not allow monitoring of early migration and incorporation of endothelial progenitor cells (EPCs) into tumor neovasculature. The goals of this study were to use magnetic resonance imaging (MRI) to track the migration and incorporation of intravenously injected, magnetically labeled EPCs into the blood vessels in a rapidly growing flank tumor model and to determine whether the pattern of EPC incorporation is related to the time of injection or tumor size.


METHODS
EPCs labeled with ferumoxide-protamine sulfate (FePro) complexes were injected into mice bearing xenografted glioma, and MRI was obtained at different stages of tumor development and size.


RESULTS
Migration and incorporation of labeled EPCs into tumor neovasculature were detected as low signal intensity on MRI at the tumor periphery as early as 3 days after EPC administration in preformed tumors. However, low signal intensities were not observed in tumors implanted at the time of EPC administration until tumor size reached 1 cm at 12 to 14 days. Prussian blue staining showed iron-positive cells at the sites corresponding to low signal intensity on MRI. Confocal microscopy showed incorporation into the neovasculature, and immunohistochemistry clearly demonstrated the transformation of the administered EPCs into endothelial cells.


CONCLUSIONS
MRI demonstrated the incorporation of FePro-labeled human CD34+/AC133+ EPCs into the neovasculature of implanted flank tumors.
Arbab
Ali S
AS
Experimental Neuroimaging Section, Laboratory of Diagnostic Radiology Research, National Institutes of Health, Bethesda, Maryland, USA. saali@rad.hfh.edu
Pandit
Sunil D
SD
Anderson
Stasia A
SA
Yocum
Gene T
GT
Bur
Monica
M
Frenkel
Victor
V
Khuu
Hanh M
HM
Read
Elizabeth J
EJ
Frank
Joseph A
JA
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD; D018952:Antigens, CD34; D002460:Cell Line; D002465:Cell Movement; D003287:Contrast Media / Q000494:pharmacology; D003911:Dextrans; D005260:Female; D052203:Ferrosoferric Oxide; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007501:Iron / Q000494:pharmacology; D018810:Magnetic Resonance Angiography / Q000379:methods; D058185:Magnetite Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal / Q000379:methods; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology; D010455:Peptides
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D003287:Contrast Media; D003911:Dextrans; D006023:Glycoproteins; D058185:Magnetite Nanoparticles; D010087:Oxides; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide