In Reply: Emerging Approaches for Cardiovascular Stem Cell Imaging

Abstract

To the Editor: We appreciate the careful and thoughtful letter by Dr. Gholamrezanezhad regarding our recent review article about stem cell labeling and tracking in cardiovascular disease [1]. Dr. Gholamrezanezhad expresses two concerns that he feels were inadequately covered in the article. The first concern is about the deleterious effects of exposure of stem cells to radiotracers. As a review article, with a limitation of 50 references, we chose to highlight the most recent findings and provide our interpretation of the evolving field over the past several decades. However, with regard to references to radiotracer toxicity in our review, we cited literature that primarily discussed radionuclide reporter gene labeling [2–6]. The topic of the toxicity of direct radiotraccer labeling of stem/progenitor cells with 111-Indium oxine (and/or 111-Indium tropolone), including the manuscript by Dr. Gholamrezanezhad and coauthors cited in his letter to the editor, was studied extensively by many authors [7–10] more than 5 years ago, and, therefore, was excluded from the review to provide space for more recent topical information. But, in order to provide a response to his concerns, I would refer him to Brenner et al. [7], who studied toxicity in hematopoietic progenitor cells (HPCs), based not only on viability but also on proliferation and differentiation assays. Those authors concluded that HPCs were more susceptible to radiation-induced toxicity than endothelial progenitor cells, which were also studied by radiolabeling previously [8]. Subsequently, our group investigated the homing capabilities of canine bone marrow–derived mesenchymal stem cells (MSCs) using 111-Indium oxine and superparamagnetic iron oxide labeling [9]. Based not only on viability, but also more rigorous metabolic and differentiation assays, we concluded that the choice of labeling dose per cell was important to maintain the pluripotency and metabolic activity of MSCs. We speculated that some of the differences seen in homing capabilities by Brenner et al. [7] and Aicher et al. [8] may be related to labeling dose, ie, toxicity. Nonetheless, in doses relevant for detection using clinical SPECT scanners, MSC labeling with 111-Indium oxine could be performed without sacrificing MSC pluripotency [9]. In an elegant paper by Jin et al. [10], the authors determined that viability was maintained for 2 weeks using a detectable labeling dose of 0.14 Bq/canine MSC. Approximately 5 years later, Gholamrezanezhad et al. have published a paper using a minimum dose >5 times the recommended dose by Jin et al., and found, not surprisingly, that these doses had a negative effect on human MSC viability. One of the tenets of cellular labeling, as we paraphrased in the review by Frangioni et al. [11], is that the label be “non-toxic, sensitive, and specific, and should permit long-term follow up.” For direct radiotracer labeling, as with ionizing radiation from X-rays, any exposure of a naive stem/progenitor cell is always a concern and should be kept to the minimum possible dose. Clearly, the toxicity to 111-Indium oxine of MSCs is different than lymphocytes and other cell types. Moreover, species differences will need to be clearly evaluated. We are, however, concerned about the assumption made by Dr. Gholamrezanezhad (in the abstract cited in his letter to the editor) that radiolabeled cells administered simultaD. A. Kedziorek :D. L. Kraitchman (*) Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, MD, USA e-mail: dkraitc1@jhmi.edu