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Ex vivo MRI cell tracking of autologous mesenchymal stromal cells in an ovine osteochondral defect model

Markides, Hareklea; Newell, Karin J.; Rudorf, Heike; Ferreras, Lia Blokpoel; Dixon, James E.; Morris, Robert H.; Graves, Martin; Kaggie, Joshua; Henson, Frances; El Haj, Alicia J.

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Authors

Hareklea Markides

Karin J. Newell

Heike Rudorf

Lia Blokpoel Ferreras

JAMES DIXON JAMES.DIXON@NOTTINGHAM.AC.UK
Associate Professor

Robert H. Morris

Martin Graves

Joshua Kaggie

Frances Henson

Alicia J. El Haj



Abstract

Background
Osteochondral injuries represent a significant clinical problem requiring novel cell-based therapies to restore function of the damaged joint with the use of mesenchymal stromal cells (MSCs) leading research efforts. Pre-clinical studies are fundamental in translating such therapies; however, technologies to minimally invasively assess in vivo cell fate are currently limited. We investigate the potential of a MRI- (magnetic resonance imaging) and superparamagnetic iron oxide nanoparticle (SPION)-based technique to monitor cellular bio-distribution in an ovine osteochondral model of acute and chronic injuries.

Methods
MSCs were isolated, expanded and labelled with Nanomag, a 250-nm SPION, and using a novel cell-penetrating technique, glycosaminoglycan-binding enhanced transduction (GET). MRI visibility thresholds, cellular toxicity and differentiation potential post-labelling were assessed in vitro. A single osteochondral defect was created in the medial femoral condyle in the left knee joint of each sheep with the contralateral joint serving as the control. Cells, either GET-Nanomag labelled or unlabelled, were delivered 1 week or 4.5 weeks later. Sheep were sacrificed 7 days post implantation and immediately MR imaged using a 0.2-T MRI scanner and validated on a 3-T MRI scanner prior to histological evaluation.

Results
MRI data demonstrated a significant increase in MRI contrast as a result of GET-Nanomag labelling whilst cell viability, proliferation and differentiation capabilities were not affected. MRI results revealed evidence of implanted cells within the synovial joint of the injured leg of the chronic model only with no signs of cell localisation to the defect site in either model. This was validated histologically determining the location of implanted cells in the synovium. Evidence of engulfment of Nanomag-labelled cells by leukocytes is observed in the injured legs of the chronic model only. Finally, serum c-reactive protein (CRP) levels were measured by ELISA with no obvious increase in CRP levels observed as a result of P21-8R:Nanomag delivery.

Conclusion
This study has the potential to be a powerful translational tool with great implications in the clinical translation of stem cell-based therapies. Further, we have demonstrated the ability to obtain information linked to key biological events occurring post implantation, essential in designing therapies and selecting pre-clinical models.

Citation

Markides, H., Newell, K. J., Rudorf, H., Ferreras, L. B., Dixon, J. E., Morris, R. H., …El Haj, A. J. (2019). Ex vivo MRI cell tracking of autologous mesenchymal stromal cells in an ovine osteochondral defect model. Stem Cell Research and Therapy, 10, 1-15. https://doi.org/10.1186/s13287-018-1123-7

Journal Article Type Article
Acceptance Date Dec 25, 2018
Online Publication Date Jan 11, 2019
Publication Date Jan 11, 2019
Deposit Date Jan 16, 2019
Publicly Available Date Jan 16, 2019
Journal Stem Cell Research & Therapy
Print ISSN 1757-6512
Electronic ISSN 1757-6512
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 10
Article Number 25
Pages 1-15
DOI https://doi.org/10.1186/s13287-018-1123-7
Keywords SPIONs; MRI; Tracking; Osteochondral; Mesenchymal stromal cells; Pre-clinical. Translational
Public URL https://nottingham-repository.worktribe.com/output/1476029
Publisher URL https://stemcellres.biomedcentral.com/articles/10.1186/s13287-018-1123-7

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