Magnetic resonance imaging of stem cell–macrophage interactions with ferumoxytol and ferumoxytol‐derived nanoparticles

Focus Article

Hossein Nejadnik, Jessica Tseng, Heike Daldrup‐Link

Published Online: Feb 07 2019

DOI: 10.1002/wnan.1552

Full article on Wiley Online Library: HTML PDF

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“Off the shelf” allogeneic stem cell transplants and stem cell nano‐composites are being used for the treatment of degenerative bone diseases. However, major and minor histocompatibility antigens of therapeutic cell transplants can be recognized as foreign and lead to their rejection by the host immune system. If a host immune response is identified within the first week post‐transplant, immune modulating therapies could be applied to prevent graft failure and support engraftment. Ferumoxytol (Feraheme™) is an FDA approved iron oxide nanoparticle preparation for the treatment of anemia in patients. Ferumoxytol can be used “off label” as an magnetic resonance (MR) contrast agent, as these nanoparticles provide measurable signal changes on magnetic resonance imaging (MRI). In this focused review article, we will discuss three methods to localize and identify innate immune responses to stem cell transplants using ferumoxytol‐enhanced MRI, which are based on tracking stem cells, tracking macrophages or detecting mediators of cell death: (a) monitor MRI signal changes of ferumoxytol‐labeled stem cells in the presence or absence of innate immune responses, (b) monitor influx of ferumoxytol‐labeled macrophages into stem cell implants, and (c) monitor apoptosis of stem cell implants with caspase‐3 activatable nanoparticles. These techniques can detect transplant failure at an early stage, when immune‐modulating interventions can potentially preserve the viability of the cell transplants and thereby improve bone and cartilage repair outcomes. Approaches 1 and 2 are immediately translatable to clinical practice. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > Biosensing

Concept of in vivo stem cell–Immune system interaction in a pro‐inflammatory environment

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Concept of indirect tracking of macrophages responses via ex vivo labeling of stem cells with an activatable probe: (a) mesenchymal stromal cells (MSCs) were labeled with caspase‐3‐cleavable ferumoxytol‐AFC nanoparticles. Immune matched murine MSC or immune mismatched pig MSC were implanted into calvarial defects of experimental mice. Both implants could be localized based on the iron label of the cells. Caspase expression in immune mismatched cells cleaved the fluorophore AFC and caused green fluorescent signal. (b) Intravital microscopy (IVM) scan of viable MSC implant does not show any fluorescent signal on day 1 and 6 after implantation. By contrast, apoptosis of mismatched MSC activated the Feru‐AFC NPs as indicated by activated fluorescence signal on day 1. Corresponding quantitative FITC signal was significantly higher in apoptotic cell transplants compared to viable cell transplants. Data are displayed as mean FITC sum intensity of six cell transplants and standard errors. *p < 0.05 (c) coronal T2‐weighted MRI scan of the same immune‐matched and immune‐matched MSC implants shows significant T2‐signal on day 1 and 7 after implantation. Corresponding T2 relaxation times did not show a significant difference between immune‐matched and immune‐matched MSC during the early post‐transplant phase of 7 days. Data are displayed as mean T2 relaxation time of six cell transplants and standard deviations. *p < 0.05 (Reprinted with permission from K. Li et al. () Copyright 2018 Ivyspring International Publisher)

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Concept of in vivo tracking of macrophages: (a) experimental rats received intravenous ferumoxytol injections before stem cell implantation. At 48 hours after ferumoxytol injection, unlabeled viable and apoptotic stem cells were implanted into osteochondral defects of bilateral knee joints. Iron labeled bone marrow cells migrated into apoptotic cell transplants. (b) Sagittal T2‐weighted fast spin‐echo magnetic resonance (MR) images show hyperintense T2‐signal of unlabeled cells directly after implantation and moderate T2‐signal at 4 weeks after implantation, apparently due to minor migration of iron labeled cells into the transplant. (c) Sagittal T2‐weighted fast spin‐echo MR images show hyperintense T2‐signal of unlabeled cells directly after implantation and marked hypointense (dark) T2‐signal at 4 weeks after implantation, apparently due to migration of iron labeled cells into the transplant. (d) T2 relaxation times of the apoptotic implants showed a significant decrease compared with viable implants at week 4. Data are displayed as mean SNR data of six cell transplants and standard errors (Reprinted with permission from Khurana et al. () Copyright 2012 RSNA Journals)

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The in vivo ferumoxytol labeled mesenchymal stromal cells (MSCs) could be tracked with magnetic resonance (MR) imaging in patients. (a) an overview of the study: Patients received an intravenous injection of ferumoxytol, which is taken up by bone marrow cells. Then, the ferumoxytol‐labeled cells were aspirated from the iliac crest. The osteonecrotic bone was decompressed by drilling a channel to the osteonecrosis area, and the harvested ferumoxytol‐labeled cells were injected into the channel. (b) Iron‐labeled cell transplants can be detected in the decompression channel: Coronal T2‐weighted MRI scan of the left hip joint after decompression surgery and transplantation of iron labeled cells shows areas of hypointense signal in the decompression track. Superimposed color encoded T2 signal map shows iron‐labeled cells displayed by blue color. T2‐weighted MRI scan of the left hip joint after decompression surgery and transplantation of unlabeled cells does not show hypointense signal areas in the decompression track. Superimposed color encoded T2 signal map does not show iron signal in the track. Signal‐to‐noise ratios (SNR) and T2* relaxation time of unlabeled cell transplants were significantly higher compared to labeled cell transplants. Data are displayed as mean SNR and T2* relaxation time data of nine patients and standard errors. *p < 0.05 and **p < 0.01 (reprinted with permission from (Theruvath et al., ) copyright rights 2018 managed by American Association for Cancer Research)

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Concept of indirect detection of apoptosis of stem cell in vivo by magnetic resonance (MR) imaging: (a) mesenchymal stromal cells (MSCs) were labeled in vitro with ferumoxytol. Viable or apoptotic stem cell were seeded in scaffold and implanted into osteochondral defects. (b) Iron‐labeled viable MSC showed hypointense T2‐signal directly after implantation and moderate T2‐signal at 2 weeks after implantation, apparently due to slow iron metabolism. (c) Iron labeled apoptotic MSC showed hypointense T2‐signal directly after implantation and loss of T2‐signal at 2 weeks after implantation, apparently due to loss of iron labeled cells and faster iron metabolism. Histopathologies (not shown) revealed an increased number of macrophages in apoptotic implants. (d) T2 relaxation times of iron‐labeled viable, and apoptotic MASIs demonstrated a significant difference at day 14. Data are displayed as mean T2 relaxation times of five cell transplants per group and standard errors. *p < 0.05 (Reprinted with permission from Nejadnik et al. (). Copyright 2016 Nature Publishing Group)

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