In Vivo Tracking of Human Neural Progenitor Cells in the Rat Brain Using Magnetic Resonance Imaging is Not Enhanced by Ferritin Expression

Abstract

Rapid growth in the field of stem cell research has generated a lot of interest in their therapeutic use, especially in the treatment of neurodegenerative diseases. Specifically, human neural progenitor cells (hNPCs), unique in their capability to differentiate into cells of the neural lineage, have been widely investigated due to their ability to survive, thrive, and migrate toward injured tissues. Still, one of the major roadblocks for clinical applicability arises from the inability to monitor these cells following transplantation. Molecular imaging techniques, such as magnetic resonance imaging (MRI), have been explored to assess hNPC transplant location, migration, and survival. Here we investigated whether inducing hNPCs to overexpress ferritin (hNPCsFer), an iron storage protein, is sufficient to track these cells long term in the rat striatum using MRI. We found that increased hypointensity on MRI images could establish hNPCFer location. Unexpectedly, however, wild-type hNPC transplants were detected in a similar manner, which is likely due to increased iron accumulation following transplantation-induced damage. Hence, we labeled hNPCs with superparamagnetic iron oxide (SPIO) nanoparticles to further increase iron content in an attempt to enhance cell contrast in MRI. SPIO-labeling of hNPCs (hNPCs-SPIO) achieved increased hypointensity, with significantly greater area of decreased T2* compared to hNPCFer (p < 0.0001) and all other controls used. However, none of the techniques could be used to determine graft rejection in vivo, which is imperative for understanding cell behavior following transplantation. We conclude that in order for cell survival to be monitored in preclinical and clinical settings, another molecular imaging technique must be employed, including perhaps multimodal imaging, which would utilize MRI along with another imaging modality.

Ferumoxytol Labeling of Human Neural Progenitor Cells for Diagnostic Cellular Tracking in the Porcine Spinal Cord with Magnetic Resonance Imaging

“…Furthermore, no correlation was observed between MR signal and cell graft survival. All rejected cell grafts retained histologic iron, resulting in a “false positive” indicator of cell survival, which makes drawing conclusions about transplanted cell graft viability from histological iron challenging, as was shown in previous studies . However, it is still possible to use the histological iron as an indicator of graft location because it correlated with graft location confirmed with human nuclear staining.…”

“…Reporter gene systems have been designed for bioluminescence imaging , optical imaging , positron emission tomography (PET) , and MR imaging (MRI) . Exogenous contrast agents, including radionuclides for PET and superparamagnetic iron oxide nanoparticles (SPIONs) for MRI, have been used to physically label cells prior to transplantation and represent a less invasive alternative to reporter gene systems , . SPIONs are under investigation as a molecular imaging contrast agent for labeling and tracking transplanted cells with MRI , .…”

Nanotechnology for Neuroscience: Promising Approaches for Diagnostics, Therapeutics and Brain Activity Mapping

“…Another study using SPIO labelling of hNPCs in vivo, however, found that it was not a viable imaging technique as it could not determine graft rejection in vivo, which is of utmost importance in understanding cell behavior post-transplantation. [146] This highlights the variability in the results of in vitro and in vivo studies, concordant with the known complexity of biological systems.…”

Characterization of Magneto-Endosymbionts as MRI Cell Labeling and Tracking Agents

“…SPIO-based cell tracking agents have a few limitations that have prevented more widespread usage. In vivo , through apoptosis or exocytosis, SPIOs can label tissue or phagocytic cell types resulting in false positive signals not representative of the target cells; in other words, SPIOs lack live cell specificity [8]. In rapidly dividing cell types, the concentration decreases as cells divide, leading to eventual loss of signal which limits longitudinal studies.…”

“…Even without synchronization, MEs present a significant advantage over traditional contrast agents for in vivo cell tracking. Upon host cell death, conventional SPIOs are often taken up by other cell types, resulting in false positives [8, 26–30], whereas we have found that the signal from magnetotactic bacterial constructs loaded into mammalian cells is more completely and rapidly cleared upon cell death [24]. …”