In Vivo MRI Tracking of Mesenchymal Stromal Cells Labeled with Ultrasmall Paramagnetic Iron Oxide Particles after Intramyocardial Transplantation in Patients with Chronic Ischemic Heart Disease

Abstract

Background While regenerative stem cell therapy for ischemic heart disease has moved into phase 3 studies, little is still known about retention and migration of cell posttransplantation. In human studies, the ability to track transplanted cells has been limited to labeling with radioisotopes and tracking using nuclear imaging. This method is limited by low resolution and short half-lives of available radioisotopes. Longitudinal tracking using magnetic resonance imaging (MRI) of myocardial injected cells labeled with iron oxide nanoparticles has shown promising results in numerous preclinical studies but has yet to be evaluated in human studies. We aimed to evaluate MRI tracking of mesenchymal stromal cells (MSCs) labeled with ultrasmall paramagnetic iron oxide (USPIO) nanoparticles after intramyocardial transplantation in patients with ischemic heart disease (IHD). Methods Five no-option patients with chronic symptomatic IHD underwent NOGA-guided intramyocardial transplantation of USPIO-labeled MSCs. Serial MRI scans were performed to track labeled cells both visually and using semiautomated T2∗ relaxation time analysis. For safety, we followed symptoms, quality of life, and myocardial function for 6 months. Results USPIO-labeled MSCs were tracked for up to 14 days after transplantation at injection sites both visually and using semiautomated regional T2∗ relaxation time analysis. Labeling of MSCs did not impair long-term safety of treatment. Conclusion This was a first-in-man clinical experience aimed at evaluating the utility of MRI tracking of USPIO-labeled bone marrow-derived autologous MSCs after intramyocardial injection in patients with chronic IHD. The treatment was safe, and cells were detectable at injection sites up to 14 days after transplantation. Further studies are needed to clarify if MSCs migrate out of the injection area into other areas of the myocardium or if injected cells are washed out into the peripheral circulation. The trial is registered with ClinicalTrials.gov NCT03651791.

Iron Oxide Nanoparticles in Mesenchymal Stem Cell Detection and Therapy

“…Mathiasen et al conducted the first contextual clinical study in human that evaluated the usage of dextran-coated TAT-conjugated IONP-labelled autologous BM-MSCs in intramyocardial transplantation of these cells in patients with chronic ischemic heart disease. Labelled MSCs could be tracked via MRI for up to 14 days after transplantation without compromising on safety [ 88 ].…”

“… • To assist incorporation into cells, IONPs could be cross-linked with a signal peptide/cell penetrating peptide that facilitate membrane translocation (e.g. HIV1- Tat protein) [ 36 , 88 ]. • Transfection agents (protamine sulphate, lipofectamine & poly-lysine) have been used to facilitate IONP entry into MSCs and enhance cell/tissue visualisation by MRI.…”

Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering

“…In addition to the numerous and promising research results on monitoring stem cell-based treatment of cardiovascular diseases using IONP-loaded cells, first clinical studies have now been launched. In one trial, administration of ultra-small IONP-labeled autologous BM-MSCs after intramyocardial injection in patients with chronic ischemic heart disease was shown to be safe and the cells were detectable at the injection sites by MRI for up to two weeks after transplantation [ 252 ].…”

Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases

“…The MSC-HF trial assessed autologous BM-MSCs therapy in a larger number of patients with severe ischemic HF and an improvement in left ventricular end-systolic volume and ejection fraction was observed in patients treated with MSCs [ 116 ]. Recently, a published trial demonstrated that autologous BM-MSCs labelled with paramagnetic particles injected in the myocardium of patients with chronic ischemic heart disease was detectable up to 14 days after transplantation [ 117 ]. Results of the recent double-blinded multi-centered CONCERT-HF trial, that analyzed the safety and efficacy of transendocardial injection of autologous BM-MSCs along with c-kit positive cardiac cells (CPCs) showed a reduced incidence of major adverse cardiac events during the 12 months of follow-up in patients with ischemic cardiomyopathy.…”