Abstract

IntroductionThe application of mesenchymal stem cells (MSCs) in treating rheumatoid arthritis (RA) has been made possible by the immunosuppressive and differentiation abilities of these cells. A non-invasive means of assessing cell integration and bio-distribution is fundamental in evaluating the risks and success of this therapy, thereby enabling clinical translation. This paper defines the use of superparamagnetic iron oxide nanoparticles (SPIONs) in conjunction with magnetic resonance imaging (MRI) to image and track MSCs in vivo within a murine model of RA.MethodsMurine MSCs (mMSCs) were isolated, expanded and labelled with SiMAG, a commercially available particle. In vitro MRI visibility thresholds were investigated by labelling mMSCs with SiMAG with concentrations ranging from 0 to 10 μg/ml and resuspending varying cell doses (103 to 5 × 105 cells) in 2 mg/ml collagen prior to MR-imaging. Similarly, in vivo detection thresholds were identified by implanting 3 × 105 mMSCs labelled with 0 to 10 μg/ml SiMAG within the synovial cavity of a mouse and MR-imaging. Upon RA induction, 300,000 mMSCs labelled with SiMAG (10 μg/ml) were implanted via intra-articular injection and joint swelling monitored as an indication of RA development over seven days. Furthermore, the effect of SiMAG on cell viability, proliferation and differentiation was investigated.ResultsA minimum particle concentration of 1 μg/ml (300,000 cells) and cell dose of 100,000 cells (5 and 10 μg/ml) were identified as the in vitro MRI detection threshold. Cell viability, proliferation and differentiation capabilities were not affected, with labelled populations undergoing successful differentiation down osteogenic and adipogenic lineages. A significant decrease (P < 0.01) in joint swelling was measured in groups containing SiMAG-labelled and unlabelled mMSCs implying that the presence of SPIONs does not affect the immunomodulating properties of the cells. In vivo MRI scans demonstrated good contrast and the identification of SiMAG-labelled populations within the synovial joint up to 7 days post implantation. This was further confirmed using histological analysis.ConclusionsWe have been able to monitor and track the migration of stem cell populations within the rheumatic joint in a non-invasive manner. This manuscript goes further to highlight the key characteristics (biocompatible and the ability to create significant contrast at realistic doses within a clinical relevant system) demonstrated by SiMAG that should be incorporated into the design of a new clinically approved tracking agent.

Highlights

  • The application of mesenchymal stem cells (MSCs) in treating rheumatoid arthritis (RA) has been made possible by the immunosuppressive and differentiation abilities of these cells

  • Particle uptake Particle uptake following a 24 hour passive incubation period of SiMAG with murine mesenchymal stem cells (mMSC) was confirmed by Prussian blue staining (Figure 1)

  • Effective transverse relaxation time (T2eff) was found to be shorter for higher numbers of labelled cells with this further decreasing with increasing SiMAG concentration from 1 μg/ml to 10 μg/ml (Figure 2B (i,ii))

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Summary

Introduction

The application of mesenchymal stem cells (MSCs) in treating rheumatoid arthritis (RA) has been made possible by the immunosuppressive and differentiation abilities of these cells. Advances in tissue engineering have emphasised the role of mesenchymal stem cells (MSCs) in treating autoimmune diseases, such as RA [1,2,7] Their specific self-renewal, multipotent differentiation ability (osteoblasts, chondrocytes and adipocytes), migratory, anti-inflammatory and immunosuppresssive properties are all key characteristics linked to their success in stem cell-based therapies [1,2,8,9,10]. These are modulated by the secretion of bioactive molecules. The combined secretion of these factors, their role in tissue homeostasis and repair (governed by a signalling mechanism) [2] and the cartilage forming ability of MSCs provides a trophic regenerative environment, stimulating the proliferation and differentiation of tissues to achieve intrinsic repair while protecting the neo tissue in a localised immunosuppressive manner [1,7,11]

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