MR Signal Characteristics of Viable and Apoptotic Human Mesenchymal Stem Cells in Matrix-Associated Stem Cell Implants for Treatment of Osteoarthritis

Department of Radiology and Biomedical Imaging, UCSF Medical Center, University of California, San Francisco, CA 94143, USA.
Investigative radiology (Impact Factor: 4.44). 10/2010; 45(10):634-40. DOI: 10.1097/RLI.0b013e3181ed566c
Source: PubMed


To compare magnetic resonance (MR) signal characteristics of contrast agent-labeled apoptotic and viable human mesenchymal stem cells (hMSCs) in matrix-associated stem cell implants.
hMSCs were labeled with Food and Drug Administration-approved ferumoxides nanoparticles. One group (A) remained untreated whereas a second group (B) underwent mitomycin C-induced apoptosis induction. Viability of group A and apoptosis of group B was confirmed by caspase-assays and terminal dUTP nick-end labeling (TUNEL) stains. Labeled viable hMSCs, unlabeled viable hMSCs, labeled apoptotic hMSCs, and unlabeled apoptotic hMSCs (n = 7 samples each) in an agarose scaffold were implanted into cartilage defects of porcine patellae specimens and underwent MR imaging at 7 T, using T1-weighted spin-echo sequences, T2-weighted spin-echo sequences, and T2*-weighted gradient-echo sequences. Signal-to-noise ratios (SNR) of the implants were calculated and compared between different experimental groups using linear mixed regression models.
Ferumoxides-labeled hMSCs provided a strong negative T2 and T2*-enhancement. Corresponding SNR data of labeled hMSCs were significantly lower compared with unlabeled controls (P < 0.05). Apoptosis induction resulted in a significant signal decline of ferumoxides-labeled hMSC transplants on short echo time T2-weighted spinecho sequences. SNR data of labeled apoptotic hMSCs were significantly lower compared with labeled viable hMSCs (P < 0.05).
Apoptosis of transplanted ferumoxides-labeled stem cells in cartilage defects can be visualized noninvasively by a significant signal decline on T2-weighted MR images. The described MR signal characteristics may serve as a noninvasive outcome measure for the assessment of matrix-associated stem cell implants in clinical practice. Additional studies are needed to further enhance the observed differences between viable and apoptotic cells, for example, by further optimizing the applied MR pulse sequence parameters or intracellular contrast agent concentration.

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    • "Our studies have shown that viable and apoptotic MASI demonstrate distinct signal characteristics on MR images, when the cells are labeled with iron oxide nanoparticles [15,36,37,48]. Iron oxide labeled viable MASI demonstrated an increasing area of T2-signal loss in the early post-transplant period (1-2 weeks post MASI), which correlated to stem cell expansion over a larger areaat the transplantation site. "
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    ABSTRACT: About 43 million individuals in the US currently suffer from disabilities due to arthritis. Cartilage defects are the major source of pain in the affected joints. Current treatments, whilst alleviating some of the clinical symptoms, prove insufficient to cure the underlying irreversible cartilage loss. Stem cells represent a unique source for restoration of cartilage defects. Pre-clinical and clinical trials are currently pursued to investigate the potential of various types of stem cells and stem cell derived chondrocytes to repair arthritic joints. A major challenge with all stem cell-mediated tissue regeneration approaches is death of the transplanted cells with clearance by the immune system. Our current inability to diagnose successful or unsuccessful engraftment of transplanted cells non-invasively in vivo represents a major bottleneck for the development of successful stem cell therapies. A large variety of non-invasive Magnetic Resonance (MR) imaging techniques have been developed over the last decade, which enable sensitive in vivo detection of Matrix Associated Stem Cell Implants (MASI) and early diagnosis of related complications. While initially focused on successfully harvesting cellular MR imaging approaches with easily applicable SuperParamagnetic Iron Oxide Nanoparticles (SPIO), our team began to observe details that will facilitate clinical translation. We therefore started a broader effort to define a comprehensive set of novel, clinically applicable imaging approaches for stem cell transplants in patients. We established immediately clinically applicable nanoparticle labeling techniques for tracking stem cell transplants with MR imaging; we have evaluated the long term MR signal effects of iron oxide nanoparticle labeled MASI in vivo; and we have defined distinct signal characteristics of labeled viable and apoptotic MASI. This review article will provide an overview over these efforts and discuss important implications for clinical translation.
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    • "Among various available imaging techniques for cell tracking [12], [13], [14], MR imaging has the distinct advantages of providing direct cartilage depiction with high anatomical resolution, high soft tissue contrast and no radiation exposure. In previous studies, stem cells were labeled with superparamagnetic iron oxide nanoparticles (SPIO) for their direct depiction in cartilage defects with MR imaging [15], [16], [17]. SPIO allow for cell labeling by simple incubation. "
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