Abstract
Clinical applications of mesenchymal stromal/stem cells (MSCs) to treat a myriad of diseases are currently being initiated. For MSC therapy to become common practice, basic questions about the fate of MSCs once administered need to be addressed. These include the biodistribution, survival, and differentiation of MSCs. In this chapter, several imaging techniques are described that can be used to interrogate these questions in a clinically applicable manner, and several examples are discussed. Single-photon emission computed tomography (SPECT)/radioisotope imaging and magnetic resonance imaging (MRI) cell-tracking techniques are the two modalities that likely will become mainstays in clinical practice.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- BLI:
-
Bioluminescent imaging
- FDA:
-
Food and Drug Administration
- FHBG:
-
9-(4-[18F] Fluoro-3-hydroxymethylbutyl) guanine
- FIAU:
-
1-(2-deoxy-2-fluoro-1-d-arabinofuranosyl)-5-iodouracil
- GFP:
-
Green fluorescent protein
- HSV-tk:
-
Herpes simplex virus thymidine kinase
- MI:
-
Myocardial infarct
- MSC:
-
Mesenchymal stem cell
- MRI:
-
Magnetic resonance imaging
- PET:
-
Positron emission tomography
- SPECT:
-
Single-photon emission computed tomography
- SPIO:
-
Superparamagnetic iron oxide
References
Ignowski JM, Schaffer DV (2004) Kinetic analysis and modeling of firefly luciferase as a quantitative reporter gene in live mammalian cells. Biotechnol Bioeng 86(7):827–834
Keller GA, Gould S, Deluca M, Subramani S (1987) Firefly luciferase is targeted to peroxisomes in mammalian cells. Proc Natl Acad Sci USA 84(10):3264–3268
Baggett B, Roy R, Momen S, Morgan S, Tisi L, Morse D et al (2004) Thermostability of firefly luciferases affects efficiency of detection by in vivo bioluminescence. Mol Imaging 3(4):324–332
White PJ, Squirrell DJ, Arnaud P, Lowe CR, Murray JA (1996) Improved thermostability of the North American firefly luciferase: saturation mutagenesis at position 354. Biochem J 319(Pt 2):343–350
Branchini BR, Southworth TL, Khattak NF, Michelini E, Roda A (2005) Red- and green-emitting firefly luciferase mutants for bioluminescent reporter applications. Anal Biochem 345(1):140–148
Zhao H, Doyle TC, Coquoz O, Kalish F, Rice BW, Contag CH (2005) Emission spectra of bioluminescent reporters and interaction with mammalian tissue determine the sensitivity of detection in vivo. J Biomed Opt 10(4):41210
Burgos JS, Rosol M, Moats RA, Khankaldyyan V, Kohn DB, Nelson MD Jr et al (2003) Time course of bioluminescent signal in orthotopic and heterotopic brain tumors in nude mice. Biotechniques 34(6):1184–1188
Rice BW, Cable MD, Nelson MB (2001) In vivo imaging of light-emitting probes. J Biomed Opt 6(4):432–440
Troy T, Jekic-McMullen D, Sambucetti L, Rice B (2004) Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. Mol Imaging 3(1):9–23
Ntziachristos V, Ripoll J, Wang LV, Weissleder R (2005) Looking and listening to light: the evolution of whole-body photonic imaging. Nat Biotechnol 23(3):313–320
Zacharakis G, Kambara H, Shih H, Ripoll J, Grimm J, Saeki Y et al (2005) Volumetric Âtomography of fluorescent proteins through small animals in vivo. Proc Natl Acad Sci USA 102(51):18252–18257
Kidd S, Spaeth E, Dembinski JL, Dietrich M, Watson K, Klopp A et al (2009) Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 27(10):2614–2623, Epub 2009/08/04
Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K et al (2010) Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy 12(5):615–625, Epub 2010/03/17
Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A et al (2009) Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med 11(5):373–381, Epub 2009/03/11
van der Bogt KE, Sheikh AY, Schrepfer S, Hoyt G, Cao F, Ransohoff KJ et al (2008) Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation 118(14 Suppl):S121–S129, Epub 2008/10/10
Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S et al (2007) Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 25(2):371–379
Bindslev L, Haack-Sorensen M, Bisgaard K, Kragh L, Mortensen S, Hesse B et al (2006) Labelling of human mesenchymal stem cells with indium-111 for SPECT imaging: effect on cell proliferation and differentiation. Eur J Nucl Med Mol Imaging 33(10):1171–1177, Epub 2006/06/10
Lyngbaek S, Ripa RS, Haack-Sorensen M, Cortsen A, Kragh L, Andersen CB et al (2010) Serial in vivo imaging of the porcine heart after percutaneous, intramyocardially injected 111In-labeled human mesenchymal stromal cells. Int J Cardiovasc Imaging 26(3):273–284
Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169(1):12–20, Epub 2001/05/08
Chin BB, Nakamoto Y, Bulte JW, Pittenger MF, Wahl R, Kraitchman DL (2003) 111In oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction. Nucl Med Commun 24(11):1149–1154, Epub 2003/10/22
Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P et al (2005) Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 112(10):1451–1461, Epub 2005/09/01
Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A et al (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: Âfeasibility, cell migration, and body distribution. Circulation 108(7):863–868, Epub 2003/08/06
Hwang do W, Jang SJ, Kim YH, Kim HJ, Shim IK, Jeong JM et al (2008) Real-time in vivo monitoring of viable stem cells implanted on biocompatible scaffolds. Eur J Nucl Med Mol Imaging 35(10):1887–1898, Epub 2008/04/26
Tjuvajev JG, Stockhammer G, Desai R, Uehara H, Watanabe K, Gansbacher B et al (1995) Imaging the expression of transfected genes in vivo. Cancer Res 55(24):6126–6132
Ivanova A, Ponomarev V, Ageyeva I, Doubrovin M, Serganova I, Vider E et al (2002) Imaging adoptive stem cell therapy with HSV-tk/GFP reporter gene. Mol Imaging 1:208–209
Koehne G, Doubrovin M, Doubrovina E, Zanzonico P, Gallardo HF, Ivanova A et al (2003) Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes. Nat Biotechnol 21(4):405–413
Dubey P, Su H, Adonai N, Du S, Rosato A, Braun J et al (2003) Quantitative imaging of the T cell antitumor response by positron-emission tomography. Proc Natl Acad Sci USA 100(3):1232–1237
Roelants V, Labar D, de Meester C, Havaux X, Tabilio A, Gambhir SS et al (2008) Comparison between adenoviral and retroviral vectors for the transduction of the thymidine kinase PET reporter gene in rat mesenchymal stem cells. J Nucl Med 49(11):1836–1844, Epub 2008/11/06
Willmann JK, Paulmurugan R, Rodriguez-Porcel M, Stein W, Brinton TJ, Connolly AJ et al (2009) Imaging gene expression in human mesenchymal stem cells: from small to large animals. Radiology 252(1):117–127, Epub 2009/04/16
Tjuvajev JG, Finn R, Watanabe K, Joshi R, Oku T, Kennedy J et al (1996) Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy. Cancer Res 56(18):4087–4095
Chung JK (2002) Sodium iodide symporter: its role in nuclear medicine. J Nucl Med 43(9):1188–1200
Yaghoubi SS, Jensen MC, Satyamurthy N, Budhiraja S, Paik D, Czernin J et al (2009) Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat Clin Pract Oncol 6(1):53–58, Epub 2008/11/19
Bulte JW, Kraitchman DL (2004) Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 17(7):484–499, Epub 2004/11/05
Bulte JW, Douglas T, Witwer B, Zhang SC, Strable E, Lewis BK et al (2001) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19(12):1141–1147, Epub 2001/12/04
Hinds KA, Hill JM, Shapiro EM, Laukkanen MO, Silva AC, Combs CA et al (2003) Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood 102(3):867–872, Epub 2003/04/05
Sutton EJ, Henning TD, Boddington S, Demos S, Krug C, Meier R et al (2010) In vivo magnetic resonance imaging and optical imaging comparison of viable and nonviable mesenchymal stem cells with a bifunctional label. Mol Imaging 9(5):278–290, Epub 2010/09/28
Henning TD, Sutton EJ, Kim A, Golovko D, Horvai A, Ackerman L et al (2009) The influence of ferucarbotran on the chondrogenesis of human mesenchymal stem cells. Contrast Media Mol Imaging 4(4):165–173, Epub 2009/08/12
Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF et al (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107(18):2290–2293, Epub 2003/05/07
Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG et al (2008) Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke 39(5):1569–1574, Epub 2008/03/08
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I et al (2010) Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67(10):1187–1194, Epub 2010/10/13
Hauger O, Frost EE, van Heeswijk R, Deminiere C, Xue R, Delmas Y et al (2006) MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy. Radiology 238(1):200–210, Epub 2005/12/24
Ittrich H, Lange C, Togel F, Zander AR, Dahnke H, Westenfelder C et al (2007) In vivo magnetic resonance imaging of iron oxide-labeled, arterially-injected mesenchymal stem cells in kidneys of rats with acute ischemic kidney injury: detection and monitoring at 3T. J Magn Reson Imaging 25(6):1179–1191, Epub 2007/05/24
Hill JM, Dick AJ, Raman VK, Thompson RB, Yu ZX, Hinds KA et al (2003) Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108(8):1009–1014, Epub 2003/08/13
Khan M, Meduru S, Mohan IK, Kuppusamy ML, Wisel S, Kulkarni A et al (2009) Hyperbaric oxygenation enhances transplanted cell graft and functional recovery in the infarct heart. J Mol Cell Cardiol 47(2):275–287, Epub 2009/04/21
Chen A, Siow B, Blamire AM, Lako M, Clowry GJ (2010) Transplantation of magnetically labeled mesenchymal stem cells in a model of perinatal brain injury. Stem Cell Res 5(3):255–266, Epub 2010/09/30
Schafer R, Ayturan M, Bantleon R, Kehlbach R, Siegel G, Pintaske J et al (2008) The use of clinically approved small particles of iron oxide (SPIO) for labeling of mesenchymal stem cells aggravates clinical symptoms in experimental autoimmune encephalomyelitis and influences their in vivo distribution. Cell Transplant 17(8):923–941, Epub 2008/12/17
Wu X, Hu J, Zhou L, Mao Y, Yang B, Gao L et al (2008) In vivo tracking of superparamagnetic iron oxide nanoparticle-labeled mesenchymal stem cell tropism to malignant gliomas using magnetic resonance imaging. Laboratory investigation. J Neurosurg 108(2):320–329, Epub 2008/02/05
Bulte JW (2009) In vivo MRI cell tracking: clinical studies. AJR Am J Roentgenol 193(2):314–325, Epub 2009/07/22
Bulte JW, Kraitchman DL, Mackay AM, Pittenger MF (2004) Chondrogenic differentiation of mesenchymal stem cells is inhibited after magnetic labeling with ferumoxides. Blood 104(10):3410–3412; author reply 2–3. Epub 2004/11/05
Kostura L, Kraitchman DL, Mackay AM, Pittenger MF, Bulte JW (2004) Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed 17(7):513–517, Epub 2004/11/05
Boddington SE, Sutton EJ, Henning TD, Nedopil AJ, Sennino B, Kim A et al (2011) Labeling human mesenchymal stem cells with fluorescent contrast agents: the biological impact. Mol Imaging Biol 13(1):3–9, Epub 2010/04/10
Acknowledgment
The author is supported by grant MSCRFII-0161-00.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Bulte, J.W.M. (2013). In Vivo Imaging of MSCs. In: Hematti, P., Keating, A. (eds) Mesenchymal Stromal Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-5711-4_21
Download citation
DOI: https://doi.org/10.1007/978-1-4614-5711-4_21
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4614-5710-7
Online ISBN: 978-1-4614-5711-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)