The Use of Clinically Approved Small Particles of Iron Oxide (SPIO) for Labeling of Mesenchymal Stem Cells Aggravates Clinical Symptoms in Experimental Autoimmune Encephalomyelitis and Influences Their In Vivo Distribution

Abstract

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS).Mesenchymal stem cells (MSC) have been shown to ameliorate symptoms in experimental autoimmune encephalomyelitis (EAE), a model of MS. Using cloned MSC labeled with clinically approved small particles of iron oxide (SPIO) for treatment of EAE we analyzed the tissue localization of transferred cells. Treatment with unlabeled MSC led to disease amelioration compared to controls. In contrast, treatment with SPIOlabeled MSC lead to increase in disease severity. Treatment with SPIO alone did not alter disease course. After transplantation labeled and nonlabeled MSC were detected in the CNS and the liver with significantly more SPIO-labeled cells present in the CNS. Iron deposition was present in the group treated with SPIOlabeled MSC, indicating that in vivo the initially cell surface-bound iron detached from the MSC. These results could be of great importance for imaging of patients in the clinical setting, indicating that in vivo application of SPIO-labeled MSC needs to be performed with caution because the cell-derived exposure of iron can lead to disease aggravation.

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

“…were initially developed to treat EAE based on the concept that substitution of one or more amino acids to change MHC or -Martin et al, 2003;Pryce et al, 2003;Zajicek et al, 2003;Ni et al, 2004;Maresz et al, 2005;Rog et al, 2005; Freeman et al, 2006;Wissel et al, 2006; Centonze et al, 2007; Collin et al, 2007;Palazuelos et al, 2008;Zhang et al, 2009) Cell-based therapies Neural stem cells Improvement (Picard-Riera et al, 2002; Einstein et al, 2003;Pluchino et al, 2003; Einstein et al, 2006;Makar et al, 2008;Pluchino et al, 2009;Yang et al, 2009) Mesenchymal stem cells Improvement (Zappia et al, 2005; Kassis et al, 2008;Schafer et al, 2008; Bai et al, 2009;Lanza et al, 2009;Lu et al, 2009;Rafei et al, 2009; Freedman et al, 2010;Gordon et al, 2010; Karussis et al, 2010;Yamout et al, 2010) BJP CS Constantinescu et al T-cell receptor (TCR) binding characteristics would induce tolerance to the native peptide through mechanisms including T-cell antagonism and partial agonism as well as cytokine deviation (Evavold and Allen, 1991;Racioppi et al, 1993) and antagonism at the T-cell activation level (De Magistris et al, 1992). Brocke et al induced EAE with a MBP87-99-specific T-cell clone and were able to induce tolerance in vivo by treating mice with an analogue of the native peptide (alanine substitution of the phenylalanine at residue 96).…”

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

“…While most studies do not describe any significant changes in cell behavior (e. g. apoptosis rate, proliferation index, differentiation behavior) [150,151], individual studies show changes in migration behavior and the ability to form colonies [152], in cell vitality [153], in differentiation behavior [154], or in the expression pattern [152]. By the same token, the influence of cell labeling on the long-term behavior of cells and the course of disease is currently unclear [155] and must be studied more closely in the future [156]. Successful in vivo detection and migration monitoring of SPIO-labeled cells was able to be demonstrated in numerous studies, e. g. in implanted hematopoietic, mesenchymal, or neuronal stem cells in the CNS [157], heart [158], liver [159], spleen [160], bone marrow [160], kidneys [161], joints [162], and muscles [163], endothelial progenitor cells [164], transplanted islet cells [165], and lymphocytic and moncytic cells (natural killer cells in oncological cell therapies [166]).…”

Bone Marrow-Derived Human Mesenchymal Stem Cells Express Cardiomyogenic Proteins But Do Not Exhibit Functional Cardiomyogenic Differentiation Potential

“…mMSCs were trypsinized, labeled with PKH26 as described previously [31], and kept on ice until transplantation. One minute before the end of myocardial ischemia (30 min), 0.5 · 10 6 mMSCs in 50 mL saline were injected intramuscularly into the apex cordis.…”