Comment on Anderson et al, page
Since the demonstration that stem cells can track to various regions within the body and differentiate in a site-specific manner, researchers have sought to exploit them for therapy. In this issue, Anderson and colleagues use MRI to monitor the migration of these “therapeutic cells” to the neovasculature in a glioma tumor model.
For some time now in oncology, it has been recognized that angiogenesis is necessary for tumor growth and development of metastatic disease.1 More recently, bone marrow–derived endothelial progenitor cells have been implicated in the process of adult neovascularization in both physiologic and pathologic angiogenesis.2 The findings that progenitor cells are required for tumor growth and that they are actively and specifically recruited to sites of tumor-induced angiogenesis, have spawned several therapeutic schemes using these agents. Significant efforts have gone into developing these cells as “therapeutic vehicles” that would deliver a payload of anticancer biologics to the tumors by homing to and incorporating into newly forming tumor vasculature. The specific homing of these cells to neogenesis potentially will limit systemic toxicity associated with other vehicles used in gene therapy paradigms.
To move cellular transplantation therapy into the clinics, however, many aspects of the therapy need to be better elucidated. It is important to understand the temporal and spatial distribution of cells expressing a toxic or therapeutic gene product and to monitor the safety of transplants in patients. Traditional histologic analysis does not adequately address the dynamic nature of transplantation therapy creating a need for noninvasive technologies to assess the efficacy of cell transplantation in living animals in real-time. Noninvasive imaging will allow real-time monitoring of the survival, migration, and therapeutic and nontherapeutic consequences of transplanted cells.FIG1
Serial MRI in mice that received magnetically labeled Sca1+ bone marrow cells, group 2. See the complete figure in the article beginning on page .
Serial MRI in mice that received magnetically labeled Sca1+ bone marrow cells, group 2. See the complete figure in the article beginning on page .
In this issue of Blood, Anderson and colleagues have used magnetic resonance imaging (MRI) to follow magnetically labeled transplanted cells. In the reported studies, Sca1+ endothelial progenitor cells were labeled with superparamagnetic iron oxide nanoparticles (SPIOs) and then injected into the vasculature of animals. In mice with orthotopically implanted gliomas, the labeled cells tracked to the tumor periphery and were initially visible by MRI as a slight darkening surrounding the tumor 9 days after implantation. At later time points, the darkening became more pronounced and progressed to a significant hypointense ring surrounding the tumor. Ex vivo high-resolution MRI (see figure) showed that labeled cells were also infiltrating into the interior of the tumors. In temporal studies, histology demonstrated that MR signals were present only when tumors were undergoing neovascular growth, and immunohisotchemistry confirmed that iron-containing cells within the tumor and its periphery were positive for 2 endothelial cell markers, CD-31 and von Willebrand factor. Although the study did not control for the potential leakage of iron from the transplanted cells and subsequent redistribution to vasculature, there are significant data from other studies to strongly suggest that this is not the mechanism in place.3 Furthermore, the use of labeled nonviable cells for control animals supports the authors' conclusions that ex vivo–labeled progenitor cells migrate and differentiate into endothelial cells and are responsible for the signal changes observed.
Others have certainly demonstrated the use of various imaging modalities including MRI to track the migration of cells in vivo.4 However, the results of Anderson et al are very exciting because they are the first to demonstrate the utility of the approach for tracking the migration and differentiation of endothelial progenitor cells into tumor vasculature. In contrast to other noninvasive techniques used to assess microvessel density (e.g., perfusion imaging), this technology allows not only assessment of neovasculature but also the ability to noninvasively visualize functioning, genetically altered cells with resolution not obtainable by any other modality.
As science moves toward more novel approaches for delivering genes to target tissues, clinical trials will require a means to assess dosage and frequency of cell transplants in order to optimize therapy and predict outcome and side effects. Approaches such as those described by Anderson et al will be important in helping to assess these parameters in vivo.
