Letter by Sadek and Garry Regarding Article, “Iron-Oxide Labeling and Outcome of Transplanted Mesenchymal Stem Cells in the Infarcted Myocardium”
To the Editor:
We read with interest the article by Amsalem et al1 that examined the utility of superparamagnetic iron oxide nanoparticles as a labeling strategy to identify mesenchymal stem cells (MSCs) after delivery into the injured myocardium. These preclinical studies are important, as intense interest is currently focused on the use of cell therapy for patients with heart disease. In the study by Amsalem et al, the investigators demonstrated efficient labeling of the MSC population with minimal toxicity in vitro before delivery into the myocardium. The MSC population was then injected directly into immunocompetent Sprague Dawley rat hearts after ischemic injury. Four weeks after delivery, the iron oxide particles were noted to be present only in cardiac macrophages and not within the MSCs, which were undetectable with a polymerase chain reaction assay. The implication for these studies is that the iron nanoparticles that are followed after delivery (using magnetic resonance imaging or histochemical stains) are not labeling the MSCs; rather, they label the macrophages that have phagocytosed the immunogenic MSCs. The authors1 provide several limitations of the study and conclude that the “findings raise concern regarding the power of iron-labeling method in preclinical and clinical trials of cardiac cell therapy”.1 We believe this statement is misleading, as their current study has a major limitation that impacts these conclusions. The authors are correct in their predictions, provided that the cell therapy studies utilize an allogeneic source for the MSCs. Recent studies, however, have clearly demonstrated that MSCs are not immunoprivileged; rather, they mount an immunological reaction.2–5 In the study by Amsalem et al,1 the investigators used immunocompetent Sprague Dawley rats. Therefore, the delivery of immunogenic cells (MSCs) into an immunocompetent model (Sprague Dawley rat) in the absence of immunosuppression agents resulted in the complete elimination of the iron oxide nanoparticle–labeled MSCs from the recipient heart. Thus, the competent immune system of the Sprague Dawley rat may have recognized the mesenchymal cells as foreign and eliminated those cells via cellular rejection (ie, cardiac macrophages). Importantly, similar studies carried out in both porcine and rodent models clearly demonstrate that intracardiac injection of MSCs induces cellular rejection.3,5 Therefore, in this study, the iron oxide particles were phagocytosed along with the MSCs by the macrophages and thus were found within those cells at the conclusion of the experiment. On the basis of the design of this study, it may be difficult to draw conclusions about the utility of iron oxide nanoparticle labeling of autologous stem cell populations. In our opinion, it would be more appropriate to perform studies utilizing the delivery of autologous stem cells or the delivery of allogeneic stem cells in an immunocompromised host. The study by Amsalem and colleagues examined an important area of research, and further preclinical studies are warranted to address stem cell viability and labeling strategies for the cell therapy field.
Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood. 2005; 106: 4057–4065.
Grinnemo KH, Mansson A, Dellgren G, Klingberg D, Wardell E, Drvota V, Tammik C, Holgersson J, Ringden O, Sylven C, Le Blanc K. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg. 2004; 127: 1293–1300.
Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood. 2006; 108: 2114–2120.