Abstract
Purpose
A critical step in cell-based therapies is determining the exact position of transplanted cells immediately post-transplant. Here, we devised a method to detect cell transplants immediately post-transplant, using a clinical gadolinium-based contrast agent. These cells were detected as hyperintense signals using a clinically familiar T1-weighted MRI protocol.
Procedures
HEK293 cells were stably transduced to express human OATP1B3, a hepatic organic anion transporting polypeptide that transports Gd-EOB-DTPA into cells that express the transporters, the intracellular accumulation of which cells causes signal enhancement on T1-weighted MRI. Cells were pre-labeled prior to injection in media containing Gd-EOB-DTPA for MRI evaluation and indocyanine green for cryofluorescence tomography validation. Labeled cells were injected into chicken hearts, in vitro, after which MRI and cryofluorescence tomography were performed in sequence.
Results
OATP1B3-expressing cells had substantially reduced T1 following labeling with Gd-EOB-DTPA in culture. Following their implantation into chicken heart, these cells were robustly identified in T1-weighted MRI, with image-derived injection volumes of cells commensurate with intended injection volumes. Cryofluorescence tomography showed that the areas of signal enhancement in MRI overlapped with areas of indocyanine green signal, indicating that MRI signal enhancement was due to the transplanted cells.
Conclusions
OATP1B3-expressing cells can be pre-labeled with Gd-EOB-DTPA prior to injection into tissue, affording the use of clinically familiar T1-weighted MRI to robustly detect cell transplants immediately after transplant. This procedure is easily generalizable and has potential advantages over the use of iron oxide based cell labeling agents and imaging procedures.
Similar content being viewed by others
References
Slotkin JR, Cahill KS, Tharin SA, Shapiro EM (2007) Cellular magnetic resonance imaging: nanometer and micrometer size particles for noninvasive cell localization. Neurotherapeutics 4(3):428–433
Shapiro EM, Sharer K, Skrtic S, Koretsky AP (2006) In vivo detection of single cells by MRI. Magn Reson Med 55(2):242–249
Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP (2004) MRI detection of single particles for cellular imaging. Proc Natl Acad Sci USA 101(30):10901–10906
Cheng H-LM (2023) A primer on in vivo cell tracking using MRI. Front Med 10:1193459
Ahrens ET, Bulte JW (2013) Tracking immune cells in vivo using magnetic resonance imaging. Nat Rev Immunol 13(10):755–763
Kelly JJ, Saee-Marand M, Nyström NN, Evans MM, Chen Y, Martinez FM, Hamilton AM, Ronald JA (2021) Safe harbor-targeted CRISPR-Cas9 homology-independent targeted integration for multimodality reporter gene-based cell tracking. Sci Adv 7:eabc3791
Nyström NN, McRae SW, Martinez FM, Kelly JJ, Scholl TJ, Ronald JA (2023) A Genetically Encoded Magnetic Resonance Imaging Reporter Enables Sensitive Detection and Tracking of Spontaneous Metastases in Deep Tissues. Cancer Res 83(5):673–685
Nystrom NN, Hamilton AM, Xia W, Liu S, Scholl TJ, Ronald JA (2019) Longitudinal Visualization of Viable Cancer Cell Intratumoral Distribution in Mouse Models Using Oatp1a1-Enhanced Magnetic Resonance Imaging. Invest Radiol 54(5):302–311
Wu MR, Hsiao JK, Liu HM, Huang YY, Tseng YJ, Chou PT, Weng TI, Yang CY (2019) In vivo imaging of insulin-secreting human pancreatic ductal cells using MRI reporter gene technique: A feasibility study. Magn Reson Med 82(2):763–774
Wu MR, Liu HM, Lu CW, Shen WH, Lin IJ, Liao LW, Huang YY, Shieh MJ, Hsiao JK (2018) Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging. FASEB J 32(3):1705–1715
Patrick PS, Hammersley J, Loizou L, Kettunen MI, Rodrigues TB, Hu DE, Tee SS, Hesketh R, Lyons SK, Soloviev D, Lewis DY, Aime S, Fulton SM, Brindle KM (2014) Dual-modality gene reporter for in vivo imaging. Proc Natl Acad Sci USA 111(1):415–420
Wang T, Chen Y, Nystrom NN, Liu S, Fu Y, Martinez FM, Scholl TJ, Ronald JA (2023) Visualizing cell-cell communication using synthetic notch activated MRI. Proc Natl Acad Sci USA 120(11):e2216901120
Hagenbuch B, Stieger B (2013) The SLCO (former SLC21) superfamily of transporters. Mol Aspects Med 34(2–3):396–412
Leonhardt M, Keiser M, Oswald S, Kuhn J, Jia J, Grube M, Kroemer HK, Siegmund W, Weitschies W (2010) Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos 38(7):1024–1028
Planchamp C, Gex-Fabry M, Dornier C, Quadri R, Reist M, Ivancevic MK, Vallee JP, Pochon S, Terrier F, Balant L, Stieger B, Meier PJ, Pastor CM (2004) Gd-BOPTA transport into rat hepatocytes: pharmacokinetic analysis of dynamic magnetic resonance images using a hollow-fiber bioreactor. Invest Radiol 39(8):506–515
Vilgrain V, Van Beers BE, Pastor CM (2016) Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI. J Hepatol 64(3):708–716
Planchamp C, Hadengue A, Stieger B, Bourquin J, Vonlaufen A, Frossard JL, Quadri R, Becker CD, Pastor CM (2007) Function of both sinusoidal and canalicular transporters controls the concentration of organic anions within hepatocytes. Mol Pharmacol 71(4):1089–1097
Shuboni-Mulligan DD, Parys M, Blanco-Fernandez B, Mallett CL, Schnegelberger R, Takada M, Chakravarty S, Hagenbuch B, Shapiro EM (2019) Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes. Diabetes 68(2):271–280
Mir FF, Tomaszewski RP, Shuboni-Mulligan DD, Mallett CL, Hix JML, Ether ND, Shapiro EM (2019) Chimeric mouse model for MRI contrast agent evaluation. Magn Reson Med 82(1):387–394
Kiryu S, Inoue Y, Watanabe M, Izawa K, Shimada M, Tojo A, Yoshikawa K, Ohtomo K (2009) Evaluation of gadoxetate disodium as a contrast agent for mouse liver imaging: comparison with gadobenate dimeglumine. Magn Reson Imaging 27(1):101–107
Runge VM, Wells JW, Williams NM (1996) Hepatic abscesses. Magnetic resonance imaging findings using gadolinium-BOPTA. Invest Radiol 31(12):781–8
Borusewicz P, Stańczyk E, Kubiak K, Spużak J, Glińska-Suchocka K, Jankowski M, Sławuta P, Kubiak-Nowak D, Podgórski P (2019) Magnetic resonance imaging of liver tumors using gadoxetic acid (Gd-EOB-DTPA) - pilot study. BMC Vet Res 15(1):293
Benness G, Khangure M, Morris I, Warwick A, Burrows P, Vogler H (1994) Kinetics and magnetic resonance imaging of Gd-EOB-DTPA in dogs. Invest Radiol 29(Suppl 2):S177–S178
Marks AL, Hecht S, Stokes JE, Conklin GA, Deanna KH (2014) Effects of gadoxetate disodium (Eovist((R))) contrast on magnetic resonance imaging characteristics of the liver in clinically healthy dogs. Vet Radiol Ultrasound 55(3):286–291
Hix JML, Mallett CL, Latourette M, Munoz KA, Shapiro EM (2020) Dynamic contrast enhanced MRI with clinical hepatospecific MRI contrast agents in pigs: initial experience. bioRxiv 2020.02.18.946541
Bashor CJ, Hilton IB, Bandukwala H, Smith DM, Veiseh O (2022) Engineering the next generation of cell-based therapeutics. Nat Rev Drug Discovery 21(9):655–675
de Vries IJ, Lesterhuis WJ, Barentsz JO, Verdijk P, van Krieken JH, Boerman OC, Oyen WJ, Bonenkamp JJ, Boezeman JB, Adema GJ, Bulte JW, Scheenen TW, Punt CJ, Heerschap A, Figdor CG (2005) Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 23(11):1407–1413
Mallett CL, Shuboni-Mulligan DD, Shapiro EM (2018) Tracking Neural Progenitor Cell Migration in the Rodent Brain Using Magnetic Resonance Imaging. Front Neurosci 12:995
Shapiro EM, Skrtic S, Koretsky AP (2005) Sizing it up: cellular MRI using micron-sized iron oxide particles. Magn Reson Med 53(2):329–338
Aherne E, Chow K, Carr J (2020) Cardiac T(1) mapping: Techniques and applications. J Magnet Resonance Imaging : JMRI 51(5):1336–1356
Bernau K, Lewis CM, Petelinsek AM, Reagan MS, Niles DJ, Mattis VB, Meyerand ME, Suzuki M, Svendsen CN (2016) In Vivo Tracking of Human Neural Progenitor Cells in the Rat Brain Using Magnetic Resonance Imaging Is Not Enhanced by Ferritin Expression. Cell Transplant 25(3):575–592
Ziemian S, Green C, Sourbron S, Jost G, Schütz G, Hines CDG (2021) Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T. NMR Biomed 34:e4401
de Graaf W, Hausler S, Heger M, van Ginhoven TM, van Cappellen G, Bennink RJ, Kullak-Ublick GA, Hesselmann R, van Gulik TM, Stieger B (2011) Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green. J Hepatol 54(4):738–745
Hernández Lozano I, Langer O (2020) Use of imaging to assess the activity of hepatic transporters. Expert Opin Drug Metab Toxicol 16(2):149–164
Acknowledgements
We are grateful for funding from NIH R21 EB032110. We are appreciative of Catherine Connaughton’s assistance during the cell injections.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Bhattacharyya, T., Mallett, C.L. & Shapiro, E.M. MRI-Based Cell Tracking of OATP-Expressing Cell Transplants by Pre-Labeling with Gd-EOB-DTPA. Mol Imaging Biol 26, 233–239 (2024). https://doi.org/10.1007/s11307-024-01904-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11307-024-01904-2