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DITORIAL COMMENT

nabling Technologiesor Homing andngraftment of Cells forherapeutic Applications*

ai Pal Singh, PHD

tlanta, Georgia

pplication of cells to restore damaged myocardium oreduce further functional deterioration represents an impor-ant therapeutic modality for the treatment of patients withyocardial infarction and heart failure. In pre-clinical mod-

ls of myocardial infarction, delivery of bone marrow–erived progenitor cells, skeletal myoblasts, or mesenchymaltem cells improves functional recovery of infracted myo-ardium (1). Several clinical trials have also shown improvedeft ventricular function in patients receiving cell therapy2). However, other studies have not shown similar im-rovement in cardiac function following cell delivery (2).

See page 794

he contradictory results could have been due to a numberf factors influencing the therapeutic application of cells.hese include the cell type used, cell dose, timing ofelivery, site of delivery, and functional potential of cells.ata from a variety of studies have shown that only 1% to

% of the administered cells are recruited at the infarct site.he retention of cells in the target tissue is extremely lowhen delivered by the intravenous rout (3). A higher initialeposition of cells is achieved by intramyocardial delivery3). Subsequent cell death of injected cells reduces engraft-ent efficiency when measured at several days after delivery.greater efficacy is achieved at higher cell dose, suggesting

hat a higher engraftment of cells may be required forptimum efficacy. However, high cell dose also producesarger systemic circulation, which increases the safety con-erns. Thus, the inability to achieve desired cell homing andngraftment for optimum efficacy has been recognized as aundamental issue for cell-based therapies. Pre-clinical stud-es, where efficacy of cell therapy has been consistently

Editorials published in JACC: Cardiovascular Interventions reflect the views of theuthors and do not necessarily represent the views of JACC: Cardiovascular Interven-

aions or the American College of Cardiology.

From Saint Joseph’s Translational Research Institute, Atlanta, Georgia.

emonstrated, are performed using younger animals with-ut cardiovascular disease risk factors. In clinical setting, theatients receiving autologous cells, the cell engraftment isreatly impaired. It has been found that the circulatingumber of progenitor cells is greatly reduced in patientsith cardiovascular disease risk factors (4,5). When numberf risk factors is higher, there is greater reduction ofirculating progenitor cells. Circulating autologous endo-helial progenitor cells correlate with Framingham coronaryisk score (6). Furthermore, the progenitor cells fromatients with cardiovascular disease risk factor are found toe dysfunctional. For example, progenitor cells isolatedrom patients with diabetes, heart disease, stroke, and renalisease exhibit impaired homing capacity (7). Thus, en-bling technologies that can promote homing of cells at thearget site may promote efficacy of the delivered cells.

Several different experimental approaches for a greateroming and engraftment of cells at the target site are under

nvestigation (7,8). These include pre-treatment of cellsith pharmacological agents such as estrogen, statins, nitricxide donors and endothelial nitric oxide synthase activatorshat improve the impaired cellular mechanisms leading to areater homing; genetic engineering of cells by Akt generansfer, local administration of endothelial progenitor cellecruitment chemokine SDF-1, and implantation of cellsncorporated of in a matrix scaffold such as fibrin oranofibers. These methods have produced increased pro-enitor functions and their efficacy in pre-clinical models ofschemia. Their utility for cell enrichment at the target sites yet to be tested in the clinical settings.

In the study published in this issue of JACC: Cardiovas-ular Interventions, Kyrtatos et al. (9) have used endothelialrogenitor cells tagged with iron oxide superparamagneticanoparticles to enhance cell accumulation by magneticctuation. In recent years, nanoparticles have been success-ully used for drug delivery and tracking of cells in vivo. Thenvestigators first tested the superparamagnetic iron oxideanoparticle-tagged cells by using an in vitro simulationystem and demonstrated a 6-fold increase in the number ofells at the site of magnet placement after 1 h. Forchievement of directed cell accumulation, the investigatorseveloped a special magnet to enable orientation for ratarotid artery. In vivo testing produced about 5-fold higherell number in the injured carotid artery at the site of theagnetic field application. Based on these data, the inves-

igators have concluded that the study represents a proof ofoncept for the induction of cell homing using the nano-article tags. The experimental results suggest that thisould be a potential approach for enhancement of celloming, at least in tissues that can be accessible by externalagnetic force.The study, however, has a number of limitations. By

electing Endorem as the tagging material, the investigators

ssume that Endorem may be safer than the other forms of

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Editorial Comment

804

uperparamagnetic iron oxide nanoparticles. Although, En-orem is approved, by the U.S. Food and Drug Adminis-ration, for cell tracking by magnetic resonance imaging, itsafety for therapeutic use is yet to be determined. The celliability and functional activity following the ingestion ofanoparticles and magnetic force application are important

ssues. Extended magnetic application clearly leads to celleath as reported in Figure 2 of the article by Kyrtatos et al. (9).his is consistent with the known deleterious effects of ironanoparticles on cellular structures. Therefore, functional ac-ivities of the cells containing nanoparticles need to be dem-nstrated. Cellular activities such as cell proliferation, migra-ion, adhesion, spreading, in vitro angiogenesis, and cytokineene expression could be used to assess the effects of nanopar-icles and magnetic force on cell functionality.

Although, the magnetic actuation induced a 5-fold in-rease in the number of cells at the injured site, it is notnown whether an initial increase in cell number of thisagnitude is indeed adequate to improve vascular function

nd efficacy. The confocal microscopic studies were per-ormed at 24 h after cell delivery. These data indicatencreased cell accumulation in the injured artery at the sitef the magnetic field. Demonstration of vascular coverage,ell morphology, and expression of endothelial cell surfacearkers over a period of several days to weeks must be

erformed. It is important to note that a continuouseduction in cell survival and localization at the target siteccurs over time (3). Therefore, the ability of cells to survive,ngraft, and produce accelerated re-endothelialization needs toe demonstrated. The efficacy of the engrafted cells needs to beetermined by improvement in vascular function by ex vivo and

n vivo vascular reactivity.The use of the magnetic field for cell attraction also

epresents a significant limitation for its application to targetissues localized deeper in the body. A greater magneticorce will be required for targeting tissues such as those ofhe heart. Therefore, achievement of the cell engraftmentecessary for therapeutic effects by using a “safe magnetorce” would be challenging. In the current study, thenvestigators did not determine the impact of magnetic fieldn the pathophysiology of the injured carotid artery. A goodxperimental control would have been to determine theffects of the magnetic field alone on the injured carotid

rtery. For example, it was not determined if the application n

f the magnetic force to injured artery leads to increasedhrombosis, which may impact cell accumulation.

Besides the limitations and the preliminary nature of thetudy using iron oxide paramagnetic nanoparticle technol-gy, it is important to further assess its utility along withther potentially new enabling technologies currently undernvestigation for the improvement of cell homing andngraftment. This is particularly important for intravenousdministration of cells, a most convenient rout of cellelivery. Greater than 90% of the cells end up in the lungollowing intravenous delivery. The number of cells found inhe heart after a few weeks are undetectable. There lies thehallenge to enabling technologies for cell homing andngraftment.

eprint requests and correspondence: Dr. Jai Pal Singh, Chiefcientific Officer, Saint Joseph’s Translational Research Institute,tlanta, Georgia 30342. E-mail: jsingh@sjha.org.

EFERENCES

. Van der Bogt KEA, Sheikh AY, Schrepfer S, et al. Comparison ofdifferent adult stem cell types for the treatment of myocardial ischemia.Circ 2008;118:s121–8.

. Reffelmann T, Könemann S, Kloner RA, Promise of blood- and bonemarrow-derived stem cell transplantation for functional cardiac repair.Putting it in perspective with existing therapy. J Am Coll Cardiol2009;53:305–8.

. Li SH, Lai TY, Sun Z, et al. Tracking cardiac engraftment anddistribution of implanted bone marrow cells: comparing intra-aortic,intravenous, and intramyocardial delivery. J Thorac Cardiovasc Surg2009;137:1225–33.

. Dimmeler S, Leri A. Aging and disease as modifier of efficacy of celltherapy. Circ Res 2008;102:1319–30.

. Werner N, Nickenig G. Influence of cardiovascular risk factors onendothelial progenitor cells. Limitation for therapy. ArteriosclerThromb Vasc Biol 2006;26:257–66.

. Ghani U, Shuaib A, Nasir A, et al. Endothelial progenitor cells duringcerebrovascular disease. Stroke 2006;36:151–3.

. Chavakis E, Urbich C, Dimmeler S. Homing and engraftment ofprogenitor cells: a prerequisite for cell therapy. J Mol Cell Cardiol2008;454:514–22.

. Romagnani P, Lasagni L, Mazzinghi B, et al. Pharmacological modu-lation of stem cell function. Curr Med Chem 2007; 14:1129–39.

. Krytatos PG, Lehtolsinen P, Junemann-Ramirez M, et al. Magnetictagging increases delivery of circulating progenitors in vascular injury.J Am Coll Cardiol Intv 2009;2:794–802.

ey Words: cell therapy � heart disease � cell homing �

anoparticles.