This project is designed to develop a non-invasive magnetic resonance (MR) imaging technique for monitoring the in vivo viability, homing and engraftment of human mesenchymal stem cells (hMSC) in arthritic knee joints. Central aim will be to show that clinically applicable iron oxide based MR contrast media can be used to label hMSC effectively without impairment of their viability or differentiation capacity and that signal characteristics, provided by these iron oxide contrast media, may be used to diagnose a successful or non-successful hMSC engraftment in arthritic joints. The overall hypothesis is that iron oxide nanoparticles exhibit differences in signal intensity on MR images with respect to different states of biology of the investigated, transplanted stem cells and that these signal differences can be detected and quantified by MR imaging. We hypothesize, that iron oxide based MR contrast agents can yield estimates of the viability of the transplanted cells by differences in the T2-effect of intracellular iron oxides in viable cells and extracellular iron oxides, released from apoptotic cells. In a systematic, step-by-step approach, experiments will be carried out in cell cultures, then ex vivo in pig knees with focal cartilage defects, then in vivo in knee joints of rats with focal cartilage defects and, finally, in vivo in knee joints of rats with an antigen-induced arthritis. Studies are designed to investigate differences in MR signal characteristics of iron oxide nanoparticle labeled viable and apoptotic hMSC in these different experimental models and at different time intervals up to 8 weeks after labeling and/or intraarticular transplantation. Complementary optical imaging studies as well as electron microscopy, confocal microscopy, immunohistochemistry and spectrometry studies will be correlated with the MR findings. These data should elucidate biological and physicochemical changes of the investigated cells and iron oxide nanoparticles that influence the observed MR signal characteristics. Results should be immediately helpful in the preclinical assessment of new stem cell based therapies for arthritis treatment, in the design of related clinical trials for hMSC therapy of arthritis, and ultimately, in the assessment of those hMSC therapy regimens in clinical practice.

Public Health Relevance

. The development of a non-invasive imaging technique for differentiation between viable and non-viable donor stem cells is crucial for monitoring of virtually any stem cell based therapy. A better understanding of the signal behavior of contrast agent labeled viable and apoptotic hMSC on MR images could help to investigate the mechanisms that control stem cell death and lead the way to a more effective use of hMSC-based therapies for arthritis. Results should be immediately helpful in preclinical assessments of hMSC-based therapies of arthritis and other joint pathologies, in the design of related clinical trials, and later, in the assessment of those stem cell based therapies in clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054458-04
Application #
7879328
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Lester, Gayle E
Project Start
2008-09-15
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$347,045
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Toth, Gerda B; Varallyay, Csanad G; Horvath, Andrea et al. (2017) Current and potential imaging applications of ferumoxytol for magnetic resonance imaging. Kidney Int 92:47-66
Daldrup-Link, Heike E; Chan, Carmel; Lenkov, Olga et al. (2017) Detection of Stem Cell Transplant Rejection with Ferumoxytol MR Imaging: Correlation of MR Imaging Findings with Those at Intravital Microscopy. Radiology 284:495-507
Daldrup-Link, Heike E (2017) Ten Things You Might Not Know about Iron Oxide Nanoparticles. Radiology 284:616-629
Nejadnik, Hossein; Lenkov, Olga; Gassert, Florian et al. (2016) Macrophage phagocytosis alters the MRI signal of ferumoxytol-labeled mesenchymal stromal cells in cartilage defects. Sci Rep 6:25897
Daldrup-Link, Heike E; Sammet, Christina; Hernanz-Schulman, Marta et al. (2016) White Paper on P4 Concepts for Pediatric Imaging. J Am Coll Radiol 13:590-597.e2
Nejadnik, Hossein; Ye, Deju; Lenkov, Olga D et al. (2015) Magnetic resonance imaging of stem cell apoptosis in arthritic joints with a caspase activatable contrast agent. ACS Nano 9:1150-60
Nejadnik, Hossein; Diecke, Sebastian; Lenkov, Olga D et al. (2015) Improved approach for chondrogenic differentiation of human induced pluripotent stem cells. Stem Cell Rev 11:242-53
Daldrup-Link, Heike E; Nejadnik, Hossein (2014) MR Imaging of Stem Cell Transplants in Arthritic Joints. J Stem Cell Res Ther 4:165
Khurana, Aman; Chapelin, Fanny; Beck, Graham et al. (2013) Iron administration before stem cell harvest enables MR imaging tracking after transplantation. Radiology 269:186-97

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