Magnetic resonance hypointensive signal primarily originates from extracellular iron particles in the long-term tracking of mesenchymal stem cells transplanted in the infarcted myocardium

Abstract

Purpose The long-lasting hypointensities in cardiac magnetic resonance (CMR) were believed to originate from superparamagnetic iron oxide (SPIO)-engulfed macrophages during long-term stem cell tracking. However, the iron clearance capacity of the ischemic heart was limited. Therefore, we speculated that the extracellular SPIO particles may also be involved in the generation of false-positive signals. Methods and results Male swine mesenchymal stem cells (MSCs) were incubated with SPIO for 24 hours, and SPIO labeling had no significant effects on either cell viability or differentiation. In vitro studies showed that magnetic resonance failed to distinguish SPIO from living SPIO-MSCs or dead SPIO-MSCs. Two hours after the establishment of the female swine acute myocardial infarction model, 2×10 7 male SPIO-labeled MSCs (n=5) or unlabeled MSCs (n=5) were transextracardially injected into the infarcted myocardium at ten distinct sites. In vivo CMR with T2 star weighted imaging-flash-2D sequence revealed a signal void corresponding to the initial SPIO-MSC injection sites. At 6 months after transplantation, CMR identified 32 (64%) of the 50 injection sites, where massive Prussian blue-positive iron deposits were detected by pathological examination. However, iron particles were predominantly distributed in the extracellular space, and a minority was distributed within CD 68 -positive macrophages and other CD 68 -negative cells. No sex-determining region Y DNA of donor MSCs was detected. Conclusion CMR hypointensive signal is primarily caused by extracellular iron particles in the long-term tracking of transplanted MSCs after myocardial infarction. Consideration should be given to both the false-positive signal and the potential cardiac toxicity of long-standing iron deposits in the heart.

In Vivo Long-Term Tracking of Neural Stem Cells Transplanted into an Acute Ischemic Stroke model with Reporter Gene-Based Bimodal MR and Optical Imaging

“…Most importantly, cellular labeling with magnetic nanoparticles do not allow for the reliable discrimination by MRI between live and dead cells, 10 , 31 though a long-term cell tracking (even up to 6 months) has been reported by using this method. 32 The MRI signal from magnetic particles may be compounded by the extracellular particles or particles engulfed by host macrophages if the transplanted cells died. 10 , 31 Moreover, the quantification of labeled cells by MRI is an indirect technique.…”

Magnetic Nanoparticles for Targeting and Imaging of Stem Cells in Myocardial Infarction

“…One of the main drawbacks associated with SPION is its inability to distinguish between viable and nonviable cells. Recently, Huang et al [ 34 ] showed that the long lasting MR signals were mainly generated by extracellular, instead of intracellular, iron particles. The high concentrations of extracellular SPIONs arose from iron extruded from injected cells and compounded with the lack of significant iron clearance in the myocardium.…”

“… Schematic representation of generation and clearance of SPIONs in the myocardium (reproduced with permission [ 34 ]). …”

Nanoparticles‐Assisted Stem Cell Therapy for Ischemic Heart Disease

“…SPIO NPs can label stem cells in myocardium without affecting cell proliferation, differentiation, migration, and viability [ 68 , 69 ]. However, other studies demonstrated that MRI might overestimate survival rate of SPIO-labeled stem cells and could not track them for a long time, as macrophages within myocardium could phagocytose the discharged SPIO from the dead stem cells over time and result in false hypointensity on MRI [ 70 , 71 ]. Whatever, SPIO still can be applied to guide and assess the transplantation of stem cells into targeted tissue area [ 69 ].…”