Labeling of cells with ferumoxides–protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells
Abstract
Two FDA-approved agents, ferumoxides (Feridex), a suspension of superparamagnetic iron oxide (SPIO) nanoparticles and protamine sulfate, a drug used to reverse heparin anticoagulation, can be complexed and used to label cells magnetically ex vivo. Labeling stem cells with ferumoxides-protamine sulfate (FePro) complexes allows for non-invasive monitoring by MRI. However, in order for stem cell trials or therapies to be effective, this labeling technique must not inhibit the ability of cells to differentiate. In this study, we examined the effect of FePro labeling on stem cell differentiation. Viability, phenotypic expression and differential capacity of FePro labeled CD34 + hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) were compared with unlabeled control cells. Colony-forming unit (CFU) assays showed that the capacity to differentiate was equivalent for labeled and unlabeled HSC. Furthermore, labeling did not alter expression of surface phenotypic markers (CD34, CD31, CXCR4, CD20, CD3 and CD14) on HSC, as measured by flow cytometry. SDF-1-induced HSC migration and HSC differentiation to dendritic cells were also unaffected by FePro labeling. Both FePro-labeled and unlabeled MSC were cultured in chondrogenesis-inducing conditions. Alcian blue staining for proteoglycans revealed similar chondrogenic differentiation for both FePro-labeled and unlabeled cells. Furthermore, collagen X proteins, indicators of cartilage formation, were detected at similar levels in both labeled and unlabeled cell pellets. Prussian blue staining confirmed that cells in labeled pellets contained iron oxide, whereas cells in unlabeled pellets did not. It is concluded that FePro labeling does not alter the function or differentiation capacity of HSC and MSC. These data increase confidence that MRI studies of FePro-labeled HSC or MSC will provide an accurate representation of in vivo trafficking of unlabeled cells.
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Studies investigating the biological effects of typically sugar-coated SPION on dendritic cells, mesenchymal stem cells, endothelial cells and tumor cells have reported no impact on phenotype and cellular function.
“Studies investigating the biological effects of (typically sugar-coated) SPION on dendritic cells [126], mesenchymal stem cells [127, 128], endothelial cells [129, 130] and tumor cells [131] have reported no impact on phenotype and cellular function.”
From Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications (2019) · cites this paper as [127]
Cites
Romani, N., Reider, D., Heuer, M., Ebner, S., Kämpgen, E., Eibl, B., Niederwieser, D. W., & Schuler, G. (1996) · Journal of Immunological Methods · doi:10.1016/0022-1759(96)00078-6 · Cited by 1,091 · see citing works
Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells
Bulte, J. W. M., Douglas, T., Witwer, B. P., Zhang, S., Strable, E., Lewis, B. K., Zywicke, H. A., Miller, B., van Gelderen, P., Moskowitz, B. M., et al. (2001) · Nature Biotechnology · doi:10.1038/nbt1201-1141 · Cited by 1,027 · see citing works
Self-citationHoehn, M., Küstermann, E., Blunk, J. A., Wiedermann, D., Trapp, T., Wecker, S., Föcking, M., Arnold, H., Hescheler, J., Fleischmann, B. K., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.242435499 · Cited by 707 · see citing works
In Vivo Magnetic Resonance Imaging of Mesenchymal Stem Cells in Myocardial Infarction
Kraitchman, D. L., Heldman, A. W., Atalar, E., Amado, L. C., Martin, B. J., Pittenger, M. F., Hare, J. M., & Bulte, J. W. M. (2003) · Circulation · doi:10.1161/01.cir.0000070931.62772.4e · Cited by 706 · see citing works
Bender, A., Sapp, M., Schuler, G., et al. (1996) · Journal of Immunological Methods · doi:10.1016/0022-1759(96)00079-8 · Cited by 675 · see citing works
Frank, J. A., Miller, B., Arbab, A. S., et al. (2003) · Radiology · doi:10.1148/radiol.2281020638 · Cited by 647 · see citing works
Self-citationArbab, A. S., Wilson, L. B., Miller, B. R., Jordan, E. K., Lewis, B. K., Kalish, H. R., & Frank, J. A. (2003) · Radiology · doi:10.1148/radiol.2293021215 · Cited by 552 · see citing works
Self-citationBulte, J. W. M., Zhang, S.-C., van Gelderen, P., Herynek, V., Jordan, E. K., Duncan, I. D., & Frank, J. A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15256 · Cited by 531 · see citing works
Self-citationEfficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI
Arbab, A. S., Yocum, G. T., Kalish, H. R., Jordan, E. K., Anderson, S. A., Khakoo, A. Y., Read, E. J., & Frank, J. A. (2004) · Blood · doi:10.1182/blood-2004-02-0655 · Cited by 529 · see citing works
Self-citationSerial Cardiac Magnetic Resonance Imaging of Injected Mesenchymal Stem Cells
Hill, J. M., DICK, A. J., Raman, V. K., Thompson, R. B., Yu, Z., Hinds, K. A., Pessanha, B. S. S., Guttman, M. A., Varney, T. R., Martin, B. J., et al. (2003) · Circulation · doi:10.1161/01.cir.0000084537.66419.7a · Cited by 456 · see citing works
Protamine sulfate enhances lipid-mediated gene transfer
Sorgi, F., Bhattacharya, S. S., & Huang, L. (1997) · Gene Therapy · doi:10.1038/sj.gt.3300484 · Cited by 453 · see citing works
Kostura, L., Kraitchman, D. L., Mackay, A. M., et al. (2004) · NMR in Biomedicine · doi:10.1002/nbm.925 · Cited by 429 · see citing works
Heparin therapy during extracorporeal circulation
Bull, B. S., Huse, W. M., Brauer, F. S., et al. (1975) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/s0022-5223(19)41500-6 · Cited by 408 · see citing works
Hinds, K. A., Hill, J. M., Shapiro, E. M., Laukkanen, M. O., Silva, A. C., Combs, C. A., Varney, T. R., Balaban, R. S., Koretsky, A. P., & Dunbar, C. E. (2003) · Blood · doi:10.1182/blood-2002-12-3669 · Cited by 401 · see citing works
(2003) · PubMed · Cited by 357 · see citing works
Arbab, A. S., Wilson, L. B., Miller, B. R., Jordan, E. K., Bulte, J. W. M., & Frank, J. A. (2003) · Transplantation · doi:10.1097/01.tp.0000089237.39220.83 · Cited by 253 · see citing works
Self-citationArbab, A. S., Yocum, G. T., Wilson, L. B., Ashari, P., Jordan, E. K., Kalish, H. R., & Frank, J. A. (2004) · Molecular Imaging · doi:10.1162/153535004773861697 · Cited by 212 · see citing works
Self-citationFrank, J. A., Zywicke, H. A., Jordan, E. K., Mitchell, J. B., Lewis, B. K., Miller, B., Bryant, L. H., & Bulte, J. W. M. (2002) · Academic Radiology · doi:10.1016/s1076-6332(03)80271-4 · Cited by 207 · see citing works
Self-citationTargeting of Hematopoietic Progenitor Cells with MR Contrast Agents
Daldrup-Link, H. E., Rudelius, M., Oostendorp, R. A. J., Settles, M., Piontek, G., Metz, S., Rosenbrock, H., Keller, U., Heinzmann, U., Rummeny, E. J., et al. (2003) · Radiology · doi:10.1148/radiol.2283020322 · Cited by 200 · see citing works
Matuszewski, L., ten Persigehl, T., Wall, A., Schwindt, W., Tombach, B., Fobker, M., Poremba, C., Ebert, W., Heindel, W. L., & Bremer, C. (2005) · Radiology · doi:10.1148/radiol.2351040094 · Cited by 179 · see citing works
In Vivo Trafficking and Targeted Delivery of Magnetically Labeled Stem Cells
Arbab, A. S., Jordan, E. K., Wilson, L. B., Yocum, G. T., Lewis, B. K., & Frank, J. A. (2004) · Human Gene Therapy · doi:10.1089/104303404322959506 · Cited by 176 · see citing works
Self-citationMagnetic resonance imaging of labeled T‐cells in a mouse model of multiple sclerosis
Anderson, S. A., Quandt, J. A., Jordan, E. K., Arbab, A. S., Martinꝉ, R., McFarland, H. F., & Frank, J. A. (2004) · Annals of Neurology · doi:10.1002/ana.20066 · Cited by 156 · see citing works
Self-citationBulte, J. W. M., Kraitchman, D. L., Mackay, A. M., et al. (2004) · Blood · doi:10.1182/blood-2004-06-2117 · Cited by 146 · see citing works
Antineoplastic activity of poly(L-lysine) with some ascites tumor cells.
Arnold, L. J., Dagan, A., Gutheil, J. C., et al. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.7.3246 · Cited by 116 · see citing works
In vivo MRI of embryonic stem cells in a mouse model of myocardial infarction
Himes, N. C., Min, J., Lee, R., et al. (2004) · Magnetic Resonance in Medicine · doi:10.1002/mrm.20220 · Cited by 107 · see citing works
MRI of insulitis in autoimmune diabetes
Moore, A. V., Sun, P. Z., Cory, D. G., et al. (2002) · Magnetic Resonance in Medicine · doi:10.1002/mrm.10110 · Cited by 99 · see citing works
Complications of heparin therapy.
Gervin, A. S. (1975) · PubMed · Cited by 80 · see citing works
Mandl, S. J., Mari, C., Edinger, M., et al. (2004) · Molecular Imaging · doi:10.1162/153535004773861679 · Cited by 64 · see citing works
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Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications
Dadfar, S. M., Roemhild, K., Drude, N. I., von Stillfried, S., Knüchel, R., Kiessling, F., & Lammers, T. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.01.005 · Cited by 1,181 · see citing works
Magnetic tagging of therapeutic cells for MRI
Budde, M. D., & Frank, J. A. (2009) · Journal of Nuclear Medicine · doi:10.2967/jnumed.108.053546 · Cited by 78 · see citing works
Self-citationWang, Y. J., Leung, K. C., Cheung, W., Wang, H., Shi, L., Wang, D., Qin, L., & Ahuja, A. T. (2010) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.22173 · Cited by 29 · see citing works
- Authors
- Arbab, A. S., Yocum, G. T., Rad, A. M., Khakoo, A. Y., Fellowes, V., Read, E. J., & Frank, J. A.
- Affiliations
- Henry Ford Health (US)
- National Institutes of Health (US)
- Corresponding author
- Arbab, Ali S.
- Venue
- NMR in Biomedicine
- Publisher
- Wiley
- Published
- 2005-10-17
- Volume
- 18
- Issue
- 8
- Pages
- 553-559
- ISSN
- 0952-3480 (ISSN-L)
- 1099-1492
- OpenAlex
- W2031894890
- Cited by
- 297
- References
- 28
- Citations by year
- 2025: 1 · 2022: 4 · 2021: 9 · 2020: 3 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 7 · 2015: 14 · 2014: 13 · 2013: 21 · 2012: 40
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NMR in Biomedicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Physical Sciences › Engineering › Biomedical Engineering › Characterization and Applications of Magnetic Nanoparticles
- Keywords
- ferumoxides, protamine sulfate, superparamagnetic iron oxide nanoparticles, cell labeling, hematopoietic stem cells, mesenchymal stem cells, stem cell differentiation, MRI cell tracking, chondrogenic differentiation, dendritic cell differentiation, stem cell migration, cell surface markers, iron oxide nanoparticles
- MeSH terms
- Cell Differentiation, Contrast Media, Dextrans, Fetal Blood, Hematopoietic Stem Cells, Heparin Antagonists, Humans, Iron, Magnetic Resonance Imaging, Oxides, Phenotype, Protamines, Biomarkers, Ferrosoferric Oxide, Magnetite Nanoparticles, Mesenchymal Stem Cells
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