MRI and Confocal Microscopy Studies of Magnetically Labeled Endothelial Progenitor Cells Trafficking to Sites of Tumor Angiogenesis

¹ Henry Ford Health System, Detroit, Michigan
² National Institutes of Health, Bethesda, Maryland

^* To whom correspondence should be addressed. E-mail: jafrank{at}helix.nih.gov.

	Abstract

Purpose: 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 MRI to track the migration and incorporation of intravenously injected, magnetically labeled EPCs into the blood vessels in a rapidly growing flank tumor model, to determine if the pattern of EPC incorporation is related to the time of injection or tumor size. Experimental Design: EPCs labeled with ferumoxides-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 12-14 days. Prussian blue staining showed iron positive cells at the sites corresponding to low signal intensity on MRI. Confocal microcopy showed incorporation into the neovasculature and immunohistochemistry clearly demonstrated the transformation of the administered EPCs into endothelial cells. Conclusion: In conclusion, MRI demonstrated the incorporation of FePro labeled human CD34+/AC133+ EPCs into the neovasculature of implanted flank tumors.

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