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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 4
| Issue : 3 | Page : 133-138 |
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Effects of labeling human mesenchymal stem cells with superparamagnetic iron oxides on cellular functions and magnetic resonance contrast in hypoxic environments and long-term monitoring
Jens T Rosenberg1, Xuegang Yuan2, Shannon N Helsper1, F Andrew Bagdasarian1, Teng Ma2, Samuel C Grant1
1 Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering; The National High Magnetic Field Laboratory, CIMAR, Florida State University, Tallahassee, Florida, USA
2 Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA
| Date of Submission | 21-Jul-2018 |
| Date of Acceptance | 10-Sep-2018 |
| Date of Web Publication | 09-Oct-2018 |
Correspondence Address:
Dr. Teng Ma
Department of Chemical and Biomedical Engineering, Florida State University, 2525 Pottsdamer St., Tallahassee, FL, 32310
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/bc.bc_18_18
Ischemia, which involves decreased blood flow to a region and a corresponding deprivation of oxygen and nutrients, can be induced as a consequence of stroke or heart attack. A prevalent disease that affects many individuals worldwide, ischemic stroke results in functional and cognitive impairments, as neural cells in the brain receive inadequate nourishment and encounter inflammation and various other detrimental toxic factors that lead to their death. Given the scarce treatments for this disease in the clinic such as the administration of tissue plasminogen activator, which is only effective in a limited time window after the occurrence of stroke, it will be necessary to develop new strategies to ameliorate or prevent stroke-induced brain damage. Cell-based therapies appear to be a promising solution for treating ischemic stroke and many other ischemia-associated and neurodegenerative maladies. Particularly, human mesenchymal stem cells (hMSCs) are of interest for cell transplantation in stroke, given their multipotency, accessibility, and reparative abilities. To determine the fate and survival of hMSC, which will be imperative for successful transplantation therapies, these cells may be monitored using magnetic resonance imaging and transfected with superparamagnetic iron oxide (SPIO), a contrast agent that facilitates the detection of these hMSCs. This review encompasses pertinent research and findings to reveal the effects of SPIO on hMSC functions in the context of transplantation in ischemic environments and over extended time periods. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences. Keywords: Cell tracking, human mesenchymal stem cells, hypoxia, ischemia, magnetic resonance imaging, superparamagnetic iron oxide
How to cite this article:
Rosenberg JT, Yuan X, Helsper SN, Bagdasarian F A, Ma T, Grant SC. Effects of labeling human mesenchymal stem cells with superparamagnetic iron oxides on cellular functions and magnetic resonance contrast in hypoxic environments and long-term monitoring. Brain Circ 2018;4:133-8 |
How to cite this URL:
Rosenberg JT, Yuan X, Helsper SN, Bagdasarian F A, Ma T, Grant SC. Effects of labeling human mesenchymal stem cells with superparamagnetic iron oxides on cellular functions and magnetic resonance contrast in hypoxic environments and long-term monitoring. Brain Circ [serial online] 2018 [cited 2023 Jun 6];4:133-8. Available from: http://www.braincirculation.org/text.asp?2018/4/3/133/242907 |
| Introduction | |  |
Mesenchymal stem cells (MSC) are progenitor cells that are widely available from various tissues, multipotent, and able to proliferate and increase in quantity,[1],[2],[3] making them ideal for regenerating and mending adipose, cartilage, bone, and other mesenchymal-derived tissue in cell-based and tissue regeneration therapies.[4],[5] In addition, MSC release anti-inflammatory factors that abate inflammation and growth factors to repair brain injury.[6] In lieu of using cell differentiation to replace degenerated neural cells, MSC may utilize trophic factors to promote a microenvironment conducive to regenerating cells.[7] MSC are a great candidate for treating neuronal damage as they are capable of crossing the blood–brain barrier[8],[9] and thus, could possibly ameliorate diseases characterized by neurodegeneration or cerebral ischemia, including Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke.[8],[10],[11],[12],[13],[14],[15],[16],[17],[18] In fact, animals with cerebral ischemia inflicted locally through the middle cerebral artery occlusion (MCAO) experimental stroke model[13],[19],[20],[21],[22],[23] or globally through cardiac arrest[24] demonstrate diminished lesion volumes and increased functionality upon MSC administration. It is uncertain how MSC exert these effects but is speculated to be associated with MSC's ability to restore and regenerate neurons through neuroprotection,[14],[20],[21],[22],[25],[26],[27] anti-inflammation,[10],[28],[29] and angiogenesis.[11],[13] Of note, MSC transplantation therapy in humans is hindered by the ischemic microenvironment generated following stroke comprising reactive oxygen species, inflammatory factors, toxic components, and minimal nutrients, all detrimental to the survival of transplanted MSC grafts.[30]
Monitoring the fate of transplanted cells will be imperative to ensure successful administration and cell survival in cell-based therapies. Magnetic resonance imaging (MRI) can noninvasively observe cell transplants, possesses other favorable benefits, and has been previously used with MSC, making it a viable alternative to traditional histological analysis.[31],[32],[33],[34],[35],[36],[37] In general, MRI requires a contrast agent within the intracellular space of the cells to be visualized, which are usually paramagnetic agents related to superparamagnetic iron oxide (SPIO) nanoparticles. SPIO typically act as R2 or R2* agents, given that they lead to dephased proximal spins and negative contrast, thus elevating MR sensitivity. Moreover, while SPIO are deemed to be safe and express inconsequential effects on human MSC (hMSC),[38],[39],[40] varying transfection methods, times, and dosages may possibly produce unfavorable changes, as exhibited by inconclusive evidence regarding SPIO influence on the bone-related differentiation of hMSC.[41],[42],[43] SPIO's dose-dependent and long-term effects on hMSC differentiation, as well as their influence on hMSC graft survival and hMSC's potential to differentiate into various cell lines in ischemic stroke, will be crucial to ascertain in future studies.
| Transplantation of Superparamagnetic Iron Oxide-Labeled Human Mesenchymal Stem Cells | | |
hMSC have the potential for treating ischemic stroke. These cells can be transfected with an SPIO to determine how the SPIO affects hMSC function during ischemia, and subsequent MRI can evaluate how long these SPIO-labeled hMSC can be detected. Ischemic regions possess an array of toxic factors and limited nutrients and oxygen, which may affect the MRI detectability and viability of SPIO-incorporated hMSC. In addition, hMSC can survive for several days after transplantation, warranting the evaluation of their long-term detection and viability after SPIO uptake. Understanding how SPIO transfection influences hMSC and tracking the survival and fate of grafted hMSC over an extended time period will be critical for developing successful hMSC transplantation therapies for stroke and other diseases involving ischemic outcomes. During in vitro culturing of hMSC, and in in vivo animal models, SPIO exerts minimal effects on cell differentiation and proliferation. Higher initial SPIO exposure levels enhance MRI relaxation rates and contrast but are not ideal for detection over longer durations. In addition, greater SPIO doses make hMSC more susceptible to ischemia-induced damage. This review examines relevant investigations and resulting evidence that demonstrate how labeling hMSC with SPIO is suitable for MRI detection over longer periods of time and has negligible effects on which cell lineage hMSC commit to, but survivability of hMSC in ischemic and hypoxic environments may decrease with high levels of SPIO exposure.
| Discussion | | |
hMSC have previously been labeled with SPIO with no substantial changes to their differentiation and proliferation.[31],[35],[38],[44],[45] Currently, studies involving SPIO-labeled hMSC have only tracked these transplanted cells for brief periods of time, around 0–3 days following transfection with SPIO.[31],[35],[45],[46],[47] Given the possibility that hMSC can survive for longer than a week, it will be critical to evaluate their long-term detection.[20],[48] hMSC are ideal for healing ischemia-induced damage to neural tissue, as they promote anti-inflammatory events[10],[28],[29] and angiogenesis.[11],[13] However, because ischemic regions are hypoxic and lack nutrients, it will be important to determine through in vivo and in vitro studies how this affects MRI detectability and the survival of transplanted hMSC transfected with SPIO, in addition to monitoring the detection and survival of these transplanted SPIO-transfected hMSC past seven days.
As evaluated by Prussian blue staining and ICP-MS, hMSC uptake of SPIO increases in a linear fashion when directly incubated in media comprising SPIO. Cell-penetrating peptides (CPP) facilitate transfection and may result in the maximum internal concentration manifesting during the highest initial concentration.[40] Chemical manipulation may not be necessary for transfecting SPIO in hMSC, as SPIO uptake increases with additional exposure time.[33],[40],[49],[50] SPIO can be altered with antibodies and other receptors selective for certain cells,[38],[51],[52],[53] or the nonspecific CPP poly-L-lysine (PLL),[54] to help hMSC integrate SPIO. hMSC differentiation, proliferation, and viability are unaffected by iron in a concentration of 100 μg/ml. In addition, hMSC demonstrate successful detection by a 1.5-T scanner and after 24 h, incorporate 23 pg of iron per cell.[31] CPP or other agents that assist with transfection have insignificant improvements on SPIO uptake,[31] but dextran,[55],[56] liposomes,[57] lectin,[58] chitosan, starch, and polystyrene[59] can coat SPIO and increase efficacy. It is possible that adding PLL or other CPP can also coat other cells and compromise hMSC activity, although PLL can help hMSC internalize SPIO.[60],[61]
Initial hMSC interaction with SPIO is correlated with R2 and R2* relaxation, and R2 and R2* decrease as cells divide and consequently dilute SPIO concentration. Tracking transplanted cells over time in vivo with SPIO relies on contrast dilution, which can be modeled with in vitro MRI. With high-resolution and high-field MRI, hMSC detection is still possible over 14 days of culturing, even with relatively meager uptake of SPIO.[62],[63]
SPIO dilution does not necessarily correlate with the rate of R2 and R2* relaxation. In a 14-day study with cultured hMSC and SPIO, while SPIO transfection rates by hMSC and hMSC proliferation rates in culture increase linearly, R2 and R2* relaxation rates are nonlinear for the group exposed to the highest amount of iron, 56.0 μg. Between days 7 and 14, the percentage of hMSC containing SPIO significantly decrease relative to other time points, and there were similar percentages of SPIO-transfected hMSC for the 56.0 μg and 22.4 μg groups on day 14, as indicated by Prussian blue staining.[63]
hMSC given lower doses of SPIO may experience a slower decrease in SPIO labeling over time than hMSC with the highest initial amount of SPIO uptake, even though elevated relaxation rates in MRI and greater initial contrast are produced by increased SPIO labeling. Initial proliferation of cells may be influenced by greater SPIO integration by hMSC. Cell maturation, spreading, and construction of focal adhesion momentarily decrease during incubation with endothelial cells for a six day duration with increased exposure to SPIO coated with dextran.[64] In stem-like neuroprogenitor cells, elevated SPIO exposure also temporarily increases the time necessary for cell doubling. Sub-24 h in culture, ferucarbotran SPIO modulate regulators of the cell cycle and curtail peroxide in the cell to increase hMSC proliferation without any transfection facilitators.[65] Thus, increased exposure to SPIO may impact effects cell growth more significantly. Greater initial SPIO exposure promotes contrast but sacrifices MRI detection over longer durations.
Generating the ideal dosage and timing for labeling hMSC with SPIO requires understanding how these SPIO manipulate hMSC multipotent and proliferative capabilities. Long-term culturing yields no differences between iron-labeled hMSC and nonlabeled hMSC in regards to cell proliferation, and demonstrates that modifying SPIO doses has no substantial effects. In addition, doses of SPIO between 12.5 and 50 μg/mL in the presence or absence of CPP induce limited changes in hMSC growth.[40],[66] CFU-F assays and RT-PCR outcomes indicate that even initially high doses of SPIO generate inconsequential changes to the hMSC phenotype. Various in vivo and in vitro experiments show that any alterations to hMSC stem cell-related properties induced by SPIO incorporation are negligible, although MSC surface markers were not examined.[67] Flow cytometry analyses indicate that with CPP-mediated high quantities of transfected SPIO, there are only slight modifications in MSC-negative surface markers and none in positive surface markers.[40],[68],[69]
In a study with SPIO-marked hMSC, hMSC expression of ALP diminishes until day 21 after a peak on day 14, with various quantities of SPIO. A separate investigation demonstrates that in osteogenic induction media, hMSC exhibit similar ALP expression patterns after culturing for a week,[70] while another illustrates that the decline in ALP expression is dependent on the dose of SPIO.[43] While it can promote osteogenic differentiation in hMSC, ALP expression cannot dictate the magnitude of this process.[71] SPIO internalization in hMSC has little influence on hMSC committment to a specific osteogenic cell line, as demonstrated by similar expression of the Osterix and Runx-2 master osteogenic transcription factors for all doses of SPIO and following incubation for 14 days.[72],[67] Levels of calcium deposits on day 21 appear to be affected by levels of SPIO uptake, which was not observed in previous research examining calcification only in time periods under two weeks. SPIO in hMSC can conduct a deposition of calcium over longer periods of time in response to osteoinductive stimuli but have insignificant power over hMSC commitment to a specific osteogenic lineage. Future studies can elucidate the mechanism underlying calcification, as it is pertinent to cell-based therapies for ischemia-inducing diseases.[59]
Following transplantation of hMSC grafts, hMSC death ensues due to a hostile microenvironment at the ischemic lesion which consists of pro-inflammatory factors and reactive oxygen species,[30] and insufficient oxygen and nutrients. in vitro, measuring LDH secretion can be used to evaluate the extent of SPIO-transfected hMSC death after removing oxygen and serum, as a representation of hMSC viability under ischemic conditions in vivo. During the first 24 h, eliminating serum has minor effects on hMSC secretion of LDH/survival in circumstances with normal oxygen levels in vitro, but secretion sharply increases at three days. hMSC-mediated LDH release is significantly enhanced by low levels of both serum and oxygen, and the most LDH secretion following incubation for 24 h is observed in hMSC with the highest incorporation of SPIO. While the mechanism for how elevated SPIO exposure exacerbates ischemia-induced hMSC death in vitro remains uncertain, in in vivo settings with neuroprogenitor cells exposed to high amounts of SPIO, transfected dextran-coated SPIO increase reactive oxygen species by over 450% within 65 h and upregulate transferrin receptor-1 expression.[64] It is conceivable that transfection with SPIO renders hMSC more prone to injury from increased reactive oxygen species in ischemic-hypoxic settings, which can be probed in future research.
hMSC localize in lysosomes or endosomes in the perinuclear area, as indicated by MRI detection of hMSC containing SPIO conjugated with rhodamine.[40] Covalent coupling in the cytoplasm maintains the carboxyfluorescein succinimidyl ester (CFSE) label in these cells for longer durations. In the ipsilateral side to the SPIO-transfected hMSC injection and MCAO-induced stroke, accumulated iron and hMSC generate hypointense voids. MRI detection following 48 h is possible with hMSC exposed to only medium levels of SPIO, which evidently create sufficient contrast. These SPIO also produce gradients in the microscopic field, which expand signal voids to encompass numerous cells and not just single cells. Cerebral vasculature alterations induced by stroke and reperfusion-related blood flow from the site of injection to arteries in the ipsilateral hemisphere of the brain may prevent an increase in contrast in the brain's contralateral side.
Double labeling of hMSC with CFSE and SPIO conjugated with rhodamine demonstrate that the ipsilateral side of the brain where the stroke occurred contains hMSC incorporating both CFSE and SPIO, with 2.7 times more SPIO than in the contralateral side. It is probable that microglia and macrophages ingest SPIO that hMSC release on death, as unlabeled nuclei, also express rhodamine signals.[34],[63] Similarly, as transplanted neuronal stem cells labeled with SPIO and PPL proliferate and migrate, asymmetric cell division releases internalized iron particles at six days following transplantation.[39] Thus, the decline in MRI contrast and the iron release is likely attributed to the death of hMSC instead of contrast dilution facilitated by increasing hMSC quantities, given that transplanted hMSC survive for 5–10 days and do not exhibit proliferation in vivo. Systemic administration of stem cells through intravenous injection may cause more cells to be lost in various organs than if the cells were intra-arterially injected and followed a more direct avenue to the brain's ischemic site.[73],[74] Delivering hMSC labeled with SPIO to the brain is not a completely efficient and consistent process,[75] although PPL could affect this and MRI signal voids can be augmented by an iron concentration of 15–20 pg per cell following exposure to SPIO for 24 h.
Overall, hMSC can still be detected in an agarose tissue mimic over 14 days with minimal changes to differentiation and proliferation, if the shorter incubation duration and lower SPIO exposure level are sufficient. hMSC transfected with SPIO are more vulnerable to damage from hypoxic and ischemic conditions than hMSC without SPIO, which will be imperative information for conducting in vivo experiments involving ischemia-associated maladies. The current efforts to elucidate mechanisms underlying hMSC function and increase hMSC survivability in toxic ischemic environments through preconditioning methods will help advance cell-based therapies for ischemic stroke and other related diseases.
Financial support and sponsorship
This review was supported by the NIH (R01-NS102395) and the National High Magnetic Field Laboratory, which is supported by the NSF (DMR-1644779 and DMR-1157490) and the State of Florida.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 2007;67:9142-9.  |
| 2. | Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7. |
| 3. | Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970;3:393-403. |
| 4. | Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 2007;213:341-7. |
| 5. | Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006;24:1294-301. |
| 6. | Pavlichenko N, Sokolova I, Vijde S, Shvedova E, Alexandrov G, Krouglyakov P, et al. Mesenchymal stem cells transplantation could be beneficial for treatment of experimental ischemic stroke in rats. Brain Res 2008;1233:203-13. |
| 7. | Caplan AI. Why are MSCs therapeutic? New data: New insight. J Pathol 2009;217:318-24. |
| 8. | Tang Y, Yasuhara T, Hara K, Matsukawa N, Maki M, Yu G, et al. Transplantation of bone marrow-derived stem cells: A promising therapy for stroke. Cell Transplant 2007;16:159-69. |
| 9. | Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002;39:229-36. |
| 10. | Kim YJ, Park HJ, Lee G, Bang OY, Ahn YH, Joe E, et al. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia 2009;57:13-23. |
| 11. | Toyama K, Honmou O, Harada K, Suzuki J, Houkin K, Hamada H, et al. Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia. Exp Neurol 2009;216:47-55. |
| 12. | Ohtaki H, Ylostalo JH, Foraker JE, Robinson AP, Reger RL, Shioda S, et al. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses. Proc Natl Acad Sci U S A 2008;105:14638-43. |
| 13. | Onda T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab 2008;28:329-40. |
| 14. | Horita Y, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. J Neurosci Res 2006;84:1495-504. |
| 15. | Zietlow R, Lane EL, Dunnett SB, Rosser AE. Human stem cells for CNS repair. Cell Tissue Res 2008;331:301-22. |
| 16. | Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, Rustichelli D, et al. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2008;31:395-405. |
| 17. | Corti S, Locatelli F, Donadoni C, Guglieri M, Papadimitriou D, Strazzer S, et al. Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain 2004;127:2518-32. |
| 18. | Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Boccaletti R, et al. Autologous mesenchymal stem cells: Clinical applications in amyotrophic lateral sclerosis. Neurol Res 2006;28:523-6. |
| 19. | Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 2001;189:49-57. |
| 20. | Omori Y, Honmou O, Harada K, Suzuki J, Houkin K, Kocsis JD. Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats. Brain Res 2008;1236:30-8. |
| 21. | Liu H, Honmou O, Harada K, Nakamura K, Houkin K, Hamada H, et al. Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 2006;129:2734-45. |
| 22. | Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. I.V. Infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 2005;136:161-9. |
| 23. | Ukai R, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Mesenchymal stem cells derived from peripheral blood protects against ischemia. J Neurotrauma 2007;24:508-20. |
| 24. | Zheng W, Honmou O, Miyata K, Harada K, Suzuki J, Liu H, et al. Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia. Brain Res 2010;1310:8-16. |
| 25. | Honma T, Honmou O, Iihoshi S, Harada K, Houkin K, Hamada H, et al. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp Neurol 2006;199:56-66. |
| 26. | Iihoshi S, Honmou O, Houkin K, Hashi K, Kocsis JD. A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats. Brain Res 2004;1007:1-9. |
| 27. | Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, et al. Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery. Neurology 2002;59:514-23. |
| 28. | Bonfield TL, Koloze M, Lennon DP, Zuchowski B, Yang SE, Caplan AI. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am J Physiol Lung Cell Mol Physiol 2010;299:L760-70. |
| 29. | Bonfield TL, Nolan Koloze MT, Lennon DP, Caplan AI. Defining human mesenchymal stem cell efficacy in vivo. J Inflamm (Lond) 2010;7:51. |
| 30. | Copland IB, Galipeau J. Death and inflammation following somatic cell transplantation. Semin Immunopathol 2011;33:535-50. |
| 31. | Hsiao JK, Tai MF, Chu HH, Chen ST, Li H, Lai DM, et al. Magnetic nanoparticle labeling of mesenchymal stem cells without transfection agent: Cellular behavior and capability of detection with clinical 1.5 T magnetic resonance at the single cell level. Magn Reson Med 2007;58:717-24. |
| 32. | Ko IK, Song HT, Cho EJ, Lee ES, Huh YM, Suh JS, et al. In vivo MR imaging of tissue-engineered human mesenchymal stem cells transplanted to mouse: A preliminary study. Ann Biomed Eng 2007;35:101-8. |
| 33. | Delcroix GJ, Jacquart M, Lemaire L, Sindji L, Franconi F, Le Jeune JJ, et al. Mesenchymal and neural stem cells labeled with HEDP-coated SPIO nanoparticles: in vitro characterization and migration potential in rat brain. Brain Res 2009;1255:18-31. |
| 34. | Kraitchman DL, Bulte JW. Imaging of stem cells using MRI. Basic Res Cardiol 2008;103:105-13. |
| 35. | Bulte JW, Douglas T, Witwer B, Zhang SC, Strable E, Lewis BK, et al. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 2001;19:1141-7. |
| 36. | Muja N, Bulte JW. Magnetic resonance imaging of cells in experimental disease models. Prog Nucl Magn Reson Spectrosc 2009;55:61-77. |
| 37. | Bulte JW, Zhang S, van Gelderen P, Herynek V, Jordan EK, Duncan ID, et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: Magnetic resonance tracking of cell migration and myelination. Proc Natl Acad Sci U S A 1999;96:15256-61. |
| 38. | Bulte JW, Kraitchman DL. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 2004;17:484-99. |
| 39. | Walczak P, Kedziorek DA, Gilad AA, Barnett BP, Bulte JW. Applicability and limitations of MR tracking of neural stem cells with asymmetric cell division and rapid turnover: The case of the shiverer dysmyelinated mouse brain. Magn Reson Med 2007;58:261-9. |
| 40. | Kim HS, Oh SY, Joo HJ, Son KR, Song IC, Moon WK. The effects of clinically used MRI contrast agents on the biological properties of human mesenchymal stem cells. NMR Biomed 2010;23:514-22. |
| 41. | Kostura L, Kraitchman DL, Mackay AM, Pittenger MF, Bulte JW. Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed 2004;17:513-7. |
| 42. | Farrell E, Wielopolski P, Pavljasevic P, van Tiel S, Jahr H, Verhaar J, et al. Effects of iron oxide incorporation for long term cell tracking on MSC differentiation in vitro and in vivo. Biochem Biophys Res Commun 2008;369:1076-81. |
| 43. | Chen YC, Hsiao JK, Liu HM, Lai IY, Yao M, Hsu SC, et al. The inhibitory effect of superparamagnetic iron oxide nanoparticle (Ferucarbotran) on osteogenic differentiation and its signaling mechanism in human mesenchymal stem cells. Toxicol Appl Pharmacol 2010;245:272-9. |
| 44. | Bulte JW. Magnetic nanoparticles as markers for cellular MR imaging. J Magn Magn Mater 2005;289:423-7. |
| 45. | Weissleder R, Stark DD, Engelstad BL, Bacon BR, Compton CC, White DL, et al. Superparamagnetic iron oxide: Pharmacokinetics and toxicity. AJR Am J Roentgenol 1989;152:167-73. |
| 46. | Yang C, Tai M, Chen S, Wang Y, Chen Y, Hsiao J. Labeling of human mesenchymal stem cell: Comparison between paramagnetic and superparamagnetic agents. J Appl Phys 2009;105:07B314. |
| 47. | Omidkhoda A, Mozdarani H, Movasaghpoor A, Fatholah AA. Study of apoptosis in labeled mesenchymal stem cells with superparamagnetic iron oxide using neutral comet assay. Toxicol in vitro 2007;21:1191-6. |
| 48. | Komatsu K, Honmou O, Suzuki J, Houkin K, Hamada H, Kocsis JD. Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia. Brain Res 2010;1334:84-92. |
| 49. | Heyn C, Bowen CV, Rutt BK, Foster PJ. Detection threshold of single SPIO-labeled cells with FIESTA. Magn Reson Med 2005;53:312-20. |
| 50. | Bowen CV, Zhang X, Saab G, Gareau PJ, Rutt BK. Application of the static dephasing regime theory to superparamagnetic iron-oxide loaded cells. Magn Reson Med 2002;48:52-61. |
| 51. | Amstad E, Zurcher S, Mashaghi A, Wong JY, Textor M, Reimhult E. Surface functionalization of single superparamagnetic iron oxide nanoparticles for targeted magnetic resonance imaging. Small 2009;5:1334-42. |
| 52. | Weissleder R, Lee AS, Khaw BA, Shen T, Brady TJ. Antimyosin-labeled monocrystalline iron oxide allows detection of myocardial infarct: MR antibody imaging. Radiology 1992;182:381-5. |
| 53. | Weissleder R, Lee AS, Fischman AJ, Reimer P, Shen T, Wilkinson R, et al. Polyclonal human immunoglobulin G labeled with polymeric iron oxide: Antibody MR imaging. Radiology 1991;181:245-9. |
| 54. | Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, et al. Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 2003;228:480-7. |
| 55. | Dodd SJ, Williams M, Suhan JP, Williams DS, Koretsky AP, Ho C. Detection of single mammalian cells by high-resolution magnetic resonance imaging. Biophys J 1999;76:103-9. |
| 56. | Bulte JW, Hoekstra Y, Kamman RL, Magin RL, Webb AG, Briggs RW, et al. Specific MR imaging of human lymphocytes by monoclonal antibody-guided dextran-magnetite particles. Magn Reson Med 1992;25:148-57. |
| 57. | Bulte JW, Ma LD, Magin RL, Kamman RL, Hulstaert CE, Go KG, et al. Selective MR imaging of labeled human peripheral blood mononuclear cells by liposome mediated incorporation of dextran-magnetite particles. Magn Reson Med 1993;29:32-7. |
| 58. | Bulte JW, Laughlin PG, Jordan EK, Tran VA, Vymazal J, Frank JA. Tagging of T cells with superparamagnetic iron oxide: Uptake kinetics and relaxometry. Acad Radiol 1996;3 Suppl 2:S301-3. |
| 59. | Yan GP, Robinsonad L, Hogg P. Magnetic resonance imaging contrast agents: Overview and perspectives. Radiography 2006;13:1-15. |
| 60. | Arbab AS, Yocum GT, Wilson LB, Parwana A, Jordan EK, Kalish H, et al. Comparison of transfection agents in forming complexes with ferumoxides, cell labeling efficiency, and cellular viability. Mol Imaging 2004;3:24-32. |
| 61. | Schäfer R, Kehlbach R, Müller M, Bantleon R, Kluba T, Ayturan M, et al. Labeling of human mesenchymal stromal cells with superparamagnetic iron oxide leads to a decrease in migration capacity and colony formation ability. Cytotherapy 2009;11:68-78. |
| 62. | Rosenberg JT, Sachi-Kocher A, Davidson MW, Grant SC. Intracellular SPIO labeling of microglia: High field considerations and limitations for MR microscopy. Contrast Media Mol Imaging 2012;7:121-9. |
| 63. | Rosenberg JT, Sellgren K, Bejarano FC, Baird M, Davidosn M, Teng M, et al. MR contrast and biological impacts of intracellular superparamagnetic iron oxides on human mesenchymal stem cells with long-term culture and hypoxic exposure, Cytotherapy 2013;15:307-22. |
| 64. | Soenen SJ, Himmelreich U, Nuytten N, De Cuyper M. Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling. Biomaterials 2011;32:195-205. |
| 65. | Huang DM, Hsiao JK, Chen YC, Chien LY, Yao M, Chen YK, et al. The promotion of human mesenchymal stem cell proliferation by superparamagnetic iron oxide nanoparticles. Biomaterials 2009;30:3645-51. |
| 66. | Arbab AS, Bashaw LA, Miller BR, Jordan EK, Lewis BK, Kalish H, et al. Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 2003;229:838-46. |
| 67. | Balakumaran A, Pawelczyk E, Ren J, Sworder B, Chaudhry A, Sabatino M, et al. Superparamagnetic iron oxide nanoparticles labeling of bone marrow stromal (mesenchymal) cells does not affect their “stemness”. PLoS One 2010;5:e11462. |
| 68. | Crabbe A, Vandeputte C, Dresselaers T, Sacido AA, Verdugo JM, Eyckmans J, et al. Effects of MRI contrast agents on the stem cell phenotype. Cell Transplant 2010;19:919-36. |
| 69. | Reddy AM, Kwak BK, Shim HJ, Ahn C, Lee HS, Suh YJ, et al. In vivo tracking of mesenchymal stem cells labeled with a novel chitosan-coated superparamagnetic iron oxide nanoparticles using 3.0T MRI. J Korean Med Sci 2010;25:211-9. |
| 70. | Zhao F, Grayson WL, Ma T, Irsigler A. Perfusion affects the tissue developmental patterns of human mesenchymal stem cells in 3D scaffolds. J Cell Physiol 2009;219:421-9. |
| 71. | Kim J, Ma T. Perfusion regulation of hMSC microenvironment and osteogenic differentiation in 3D scaffold. Biotechnol Bioeng 2012;109:252-61. |
| 72. | Lee JH, Jung MJ, Hwang YH, Lee YJ, Lee S, Lee DY, et al. Heparin-coated superparamagnetic iron oxide for in vivo MR imaging of human MSCs. Biomaterials 2012;33:4861-71. |
| 73. | Hauger O, Frost EE, van Heeswijk R, Deminière C, Xue R, Delmas Y, et al. MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy. Radiology 2006;238:200-10. |
| 74. | Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, et al. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 2005;112:1451-61. |
| 75. | Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, et al. Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke 2008;39:1569-74. |
|
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