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, 2×10⁷ 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 CD₆₈-positive macrophages and other CD₆₈-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.

Keywords:

• superparamagnetic iron oxide nanoparticles
• SPIO
• cardiac magnetic resonance (CMR)
• stem cells tracking
• extracellular iron particles
• myocardial infarction (MI)

Acknowledgments

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (grants 81370003, 81470467, 81000043, 81300095, and 81400318), the Natural Science Foundation of Shanghai Municipality of China (grant 15ZR1434100), and the Science and Technology Commission of Shanghai Municipality (grant 13JC1401703).

Disclosure

The authors declare no conflicts of interest in this work.