Enabling Technologies for Homing and Engraftment of Cells for Therapeutic Applications*
Jai Pal Singh, PhD*
Saint Joseph's Translational Research Institute, Atlanta, Georgia
Key Words: cell therapy • heart disease • cell homing • nanoparticles
Application of cells to restore damaged myocardium or reduce further functional deterioration represents an important therapeutic modality for the treatment of patients with myocardial infarction and heart failure. In pre-clinical models of myocardial infarction, delivery of bone marrow–derived progenitor cells, skeletal myoblasts, or mesenchymal stem cells improves functional recovery of infracted myocardium (1). Several clinical trials have also shown improved left ventricular function in patients receiving cell therapy (2). However, other studies have not shown similar improvement in cardiac function following cell delivery (2). The contradictory results could have been due to a number of factors influencing the therapeutic application of cells. These include the cell type used, cell dose, timing of delivery, site of delivery, and functional potential of cells. Data from a variety of studies have shown that only 1% to 3% of the administered cells are recruited at the infarct site. The retention of cells in the target tissue is extremely low when delivered by the intravenous rout (3). A higher initial deposition of cells is achieved by intramyocardial delivery (3). Subsequent cell death of injected cells reduces engraftment efficiency when measured at several days after delivery. A greater efficacy is achieved at higher cell dose, suggesting that a higher engraftment of cells may be required for optimum efficacy. However, high cell dose also produces larger systemic circulation, which increases the safety concerns. Thus, the inability to achieve desired cell homing and engraftment for optimum efficacy has been recognized as a fundamental issue for cell-based therapies. Pre-clinical studies, where efficacy of cell therapy has been consistently demonstrated, are performed using younger animals without cardiovascular disease risk factors. In clinical setting, the patients receiving autologous cells, the cell engraftment is greatly impaired. It has been found that the circulating number of progenitor cells is greatly reduced in patients with cardiovascular disease risk factors (4,5). When number of risk factors is higher, there is greater reduction of circulating progenitor cells. Circulating autologous endothelial progenitor cells correlate with Framingham coronary risk score (6). Furthermore, the progenitor cells from patients with cardiovascular disease risk factor are found to be dysfunctional. For example, progenitor cells isolated from patients with diabetes, heart disease, stroke, and renal disease exhibit impaired homing capacity (7). Thus, enabling technologies that can promote homing of cells at the target site may promote efficacy of the delivered cells.
Several different experimental approaches for a greater homing and engraftment of cells at the target site are under investigation (7,8). These include pre-treatment of cells with pharmacological agents such as estrogen, statins, nitric oxide donors and endothelial nitric oxide synthase activators that improve the impaired cellular mechanisms leading to a greater homing; genetic engineering of cells by Akt gene transfer, local administration of endothelial progenitor cell recruitment chemokine SDF-1, and implantation of cells incorporated of in a matrix scaffold such as fibrin or nanofibers. These methods have produced increased progenitor functions and their efficacy in pre-clinical models of ischemia. Their utility for cell enrichment at the target site is yet to be tested in the clinical settings.
In the study published in this issue of JACC: Cardiovascular Interventions, Kyrtatos et al. (9) have used endothelial progenitor cells tagged with iron oxide superparamagnetic nanoparticles to enhance cell accumulation by magnetic actuation. In recent years, nanoparticles have been successfully used for drug delivery and tracking of cells in vivo. The investigators first tested the superparamagnetic iron oxide nanoparticle-tagged cells by using an in vitro simulation system and demonstrated a 6-fold increase in the number of cells at the site of magnet placement after 1 h. For achievement of directed cell accumulation, the investigators developed a special magnet to enable orientation for rat carotid artery. In vivo testing produced about 5-fold higher cell number in the injured carotid artery at the site of the magnetic field application. Based on these data, the investigators have concluded that the study represents a proof of concept for the induction of cell homing using the nanoparticle tags. The experimental results suggest that this could be a potential approach for enhancement of cell homing, at least in tissues that can be accessible by external magnetic force.
The study, however, has a number of limitations. By selecting Endorem as the tagging material, the investigators assume that Endorem may be safer than the other forms of superparamagnetic iron oxide nanoparticles. Although, Endorem is approved, by the U.S. Food and Drug Administration, for cell tracking by magnetic resonance imaging, its safety for therapeutic use is yet to be determined. The cell viability and functional activity following the ingestion of nanoparticles and magnetic force application are important issues. Extended magnetic application clearly leads to cell death as reported in Figure 2 of the article by Kyrtatos et al. (9). This is consistent with the known deleterious effects of iron nanoparticles on cellular structures. Therefore, functional activities of the cells containing nanoparticles need to be demonstrated. Cellular activities such as cell proliferation, migration, adhesion, spreading, in vitro angiogenesis, and cytokine gene expression could be used to assess the effects of nanoparticles and magnetic force on cell functionality.
Although, the magnetic actuation induced a 5-fold increase in the number of cells at the injured site, it is not known whether an initial increase in cell number of this magnitude is indeed adequate to improve vascular function and efficacy. The confocal microscopic studies were performed at 24 h after cell delivery. These data indicate increased cell accumulation in the injured artery at the site of the magnetic field. Demonstration of vascular coverage, cell morphology, and expression of endothelial cell surface markers over a period of several days to weeks must be performed. It is important to note that a continuous reduction in cell survival and localization at the target site occurs over time (3). Therefore, the ability of cells to survive, engraft, and produce accelerated re-endothelialization needs to be demonstrated. The efficacy of the engrafted cells needs to be determined by improvement in vascular function by ex vivo and in vivo vascular reactivity.
The use of the magnetic field for cell attraction also represents a significant limitation for its application to target tissues localized deeper in the body. A greater magnetic force will be required for targeting tissues such as those of the heart. Therefore, achievement of the cell engraftment necessary for therapeutic effects by using a "safe magnet force" would be challenging. In the current study, the investigators did not determine the impact of magnetic field on the pathophysiology of the injured carotid artery. A good experimental control would have been to determine the effects of the magnetic field alone on the injured carotid artery. For example, it was not determined if the application of the magnetic force to injured artery leads to increased thrombosis, which may impact cell accumulation.
Besides the limitations and the preliminary nature of the study using iron oxide paramagnetic nanoparticle technology, it is important to further assess its utility along with other potentially new enabling technologies currently under investigation for the improvement of cell homing and engraftment. This is particularly important for intravenous administration of cells, a most convenient rout of cell delivery. Greater than 90% of the cells end up in the lung following intravenous delivery. The number of cells found in the heart after a few weeks are undetectable. There lies the challenge to enabling technologies for cell homing and engraftment.
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Footnotes
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* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. Jai Pal Singh, Chief Scientific Officer, Saint Joseph's Translational Research Institute, Atlanta, Georgia 30342 (Email: jsingh{at}sjha.org).
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REFERENCES
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