Skip to main content
SpringerLink
Log in

Tracking of Autologous VSOP-Labeled Mesenchymal Stem Cells in the Sheep Brain Using 3.0 T MRI

  • Chapter
  • First Online:
Book cover Cell-Based Therapies in Stroke

  • 926 Accesses

Abstract

Assessment of biodistribution and monitoring of cell migration processes in vivo are essential for the safety of novel cell-based therapies for ischemic stroke and early-stage clinical trials, but are mainly lacking investigation in large animal models which are closer to the situation found in human patients. This chapter reports a series of experiments which establish a MRI-sensitive labeling procedure for autologous ovine mesenchymal stem cells (MSC) and the assessment of in vivo and in vitro detection limits of the cells at 3.0 T. Cell migration was monitored after intravenous transplantation following experimental stroke in sheep. Cell detection was feasible at 3.0 T with detection limits defined at 500 cells in vitro and 1,000 cells after local stereotaxic administration in vivo. No signs for MSC homing toward the ischemic lesion were observed after systemic cell delivery. Iron-containing cells were identified in the lung and skin wounds, but not in brain parenchyma after intravenous cell delivery. These findings are in contrast to results obtained in small animal models and may indicate significant differences of MSC behavior in large organisms. They also revealed the necessity for sensitivity-enhanced MRI sequences for improved cell detection in large animals.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Arbab AS, Bashaw LA, Miller BR, Jordan EK, Bulte JW, Frank JA (2003) Intracytoplasmic tagging of cells with ferumoxides and transfection agent for cellular magnetic resonance imaging after cell transplantation: methods and techniques. Transplantation 76:1123–1130

    Article  PubMed  CAS  Google Scholar 

  • Bang OY, Lee JS, Lee PH, Lee G (2005) Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57:874–882

    Article  PubMed  Google Scholar 

  • Bao X, Feng M, Wei J, Han Q, Zhao H, Li G, Zhu Z, Xing H, An Y, Qin C, Zhao RC, Wang R (2011) Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes angiogenesis and neurogenesis after cerebral ischemia in rats. Eur J Neurosci 34:87–98

    Article  PubMed  Google Scholar 

  • Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, Battistella V, Goldenberg RC, Kasai-Brunswick T, Chagas CL, Wajnberg E, Maiolino A, Salles XS, Andre C, Mendez-Otero R, de Freitas GR (2010) Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol 221:122–128

    Article  PubMed  Google Scholar 

  • Boltze J, Forschler A, Nitzsche B, Waldmin D, Hoffmann A, Boltze CM, Dreyer AY, Goldammer A, Reischauer A, Hartig W, Geiger KD, Barthel H, Emmrich F, Gille U (2008) Permanent middle cerebral artery occlusion in sheep: a novel large animal model of focal cerebral ­ischemia. J Cereb Blood Flow Metab 28:1951–1964

    Article  PubMed  Google Scholar 

  • Bonita R, Mendis S, Truelsen T, Bogousslavsky J, Toole J, Yatsu F (2004) The global stroke ­initiative. Lancet Neurol 3:391–393

    Article  PubMed  Google Scholar 

  • Burns TC, Steinberg GK (2011) Stem cells and stroke: opportunities, challenges and strategies. Expert Opin Biol Ther 11:447–461

    Article  PubMed  Google Scholar 

  • Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M (2001) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32:1005–1011

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M (2003) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92:692–699

    Article  PubMed  CAS  Google Scholar 

  • Daadi MM, Li Z, Arac A, Grueter BA, Sofilos M, Malenka RC, Wu JC, Steinberg GK (2009) Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther 17:1282–1291

    Article  PubMed  CAS  Google Scholar 

  • Dai Y, Zeng M, Li R, Rao S, Chen C, DelProposto Z, Haacke EM, Hu J, Renate J (2011) Improving detection of siderotic nodules in cirrhotic liver with a multi-breath-hold susceptibility-weighted imaging technique. J Magn Reson Imaging 34:318–325

    Article  PubMed  Google Scholar 

  • 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 23:1407–1413

    Article  PubMed  Google Scholar 

  • Denic A, Macura SI, Mishra P, Gamez JD, Rodriguez M, Pirko I (2011) MRI in rodent models of brain disorders. Neurotherapeutics 8:3–18

    Article  PubMed  Google Scholar 

  • Ding J, Hori K, Zhang R, Marcoux Y, Honardoust D, Shankowsky HA, Tredget EE (2011) Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 in the formation of postburn hypertrophic scar (HTS). Wound Repair Regen 19:568–578

    Article  PubMed  Google Scholar 

  • Dreyer A, Stroh A, Pösel C, Findeisen M, von Geymüller T, Lobsien D, Nitzsche B, Boltze J (2012) Frameless stereotaxy in sheep – neurosurgical and imaging techniques for translational stroke research. In: Balestrino M (ed) Advances in the preclinical study of ischemic stroke, 1st edn. InTech, Rijeka

    Google Scholar 

  • Emre U, Rantanen K, Tatlisumak T (2007) Antithrombotic treatment in the prevention of ischemic stroke. Curr Drug Targets 8:817–823

    Article  PubMed  CAS  Google Scholar 

  • Falluji N, Abou-Chebl A, Rodriguez Castro CE, Mukherjee D (2012) Reperfusion strategies for acute ischemic stroke. Angiology 63:289–296

    Article  PubMed  Google Scholar 

  • Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692

    Article  PubMed  CAS  Google Scholar 

  • Frey S, Comeau R, Hynes B, Mackey S, Petrides M (2004) Frameless stereotaxy in the nonhuman primate. Neuroimage 23:1226–1234

    Article  PubMed  Google Scholar 

  • Fujio M, Yamamoto A, Ando Y, Shohara R, Kinoshita K, Kaneko T, Hibi H, Ueda M (2011) Stromal cell-derived factor-1 enhances distraction osteogenesis-mediated skeletal tissue regeneration through the recruitment of endothelial precursors. Bone 49:693–700

    Article  PubMed  CAS  Google Scholar 

  • Haacke EM, Mittal S, Wu Z, Neelavalli J, Cheng YC (2009) Susceptibility-weighted imaging: technical aspects and clinical applications, part 1. AJNR Am J Neuroradiol 30:19–30

    Article  PubMed  CAS  Google Scholar 

  • Hannoush EJ, Sifri ZC, Elhassan IO, Mohr AM, Alzate WD, Offin M, Livingston DH (2011) Impact of enhanced mobilization of bone marrow derived cells to site of injury. J Trauma 71:283–289

    Article  PubMed  Google Scholar 

  • Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, Waxman SG, Kocsis JD (2011) Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 134:1790–1807

    Article  PubMed  Google Scholar 

  • Jang KS, Lee KS, Yang SH, Jeun SS (2010) In vivo tracking of transplanted bone marrow-derived mesenchymal stem cells in a murine model of stroke by bioluminescence imaging. J Korean Neurosurg Soc 48:391–398

    Article  PubMed  Google Scholar 

  • Jensen MB, Yan H, Krishnaney-Davison R, Al SA, Zhang SC (2011) Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J Stroke Cerebrovasc Dis. PMID: 22078778

    Google Scholar 

  • Kidwell CS, Wintermark M (2008) Imaging of intracranial haemorrhage. Lancet Neurol 7:256–267

    Article  PubMed  Google Scholar 

  • Kim D, Chun BG, Kim YK, Lee YH, Park CS, Jeon I, Cheong C, Hwang TS, Chung H, Gwag BJ, Hong KS, Song J (2008) In vivo tracking of human mesenchymal stem cells in experimental stroke. Cell Transplant 16:1007–1012

    Article  PubMed  Google Scholar 

  • Kranz A, Wagner DC, Kamprad M, Scholz M, Schmidt UR, Nitzsche F, Aberman Z, Emmrich F, Riegelsberger UM, Boltze J (2010) Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats. Brain Res 1315:128–136

    Article  PubMed  CAS  Google Scholar 

  • Langhorne P, Bernhardt J, Kwakkel G (2011) Stroke rehabilitation. Lancet 377:1693–1702

    Article  PubMed  Google Scholar 

  • Lansberg MG, Bluhmki E, Thijs VN (2009) Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke 40:2438–2441

    Article  PubMed  CAS  Google Scholar 

  • Lin YC, Ko TL, Shih YH, Lin MY, Fu TW, Hsiao HS, Hsu JY, Fu YS (2011) Human umbilical mesenchymal stem cells promote recovery after ischemic stroke. Stroke 42:2045–2053

    Article  PubMed  Google Scholar 

  • Minnerup J, Kim JB, Schmidt A, Diederich K, Bauer H, Schilling M, Strecker JK, Ringelstein EB, Sommer C, Scholer HR, Schabitz WR (2011) Effects of neural progenitor cells on sensorimotor recovery and endogenous repair mechanisms after photothrombotic stroke. Stroke 42:1757–1763

    Article  PubMed  Google Scholar 

  • Muja N, Bulte JW (2009) Magnetic resonance imaging of cells in experimental disease models. Prog Nucl Magn Reson Spectrosc 55:61–77

    Article  PubMed  CAS  Google Scholar 

  • Nagai N, Kawao N, Okada K, Okumoto K, Teramura T, Ueshima S, Umemura K, Matsuo O (2010) Systemic transplantation of embryonic stem cells accelerates brain lesion decrease and angiogenesis. Neuroreport 21:575–579

    Article  PubMed  Google Scholar 

  • Natarajan SK, Snyder KV, Siddiqui AH, Ionita CC, Hopkins LN, Levy EI (2009) Safety and effectiveness of endovascular therapy after 8 hours of acute ischemic stroke onset and wake-up strokes. Stroke 40:3269–3274

    Article  PubMed  CAS  Google Scholar 

  • Okazaki T, Magaki T, Takeda M, Kajiwara Y, Hanaya R, Sugiyama K, Arita K, Nishimura M, Kato Y, Kurisu K (2008) Intravenous administration of bone marrow stromal cells increases survivin and Bcl-2 protein expression and improves sensorimotor function following ischemia in rats. Neurosci Lett 430:109–114

    Article  PubMed  CAS  Google Scholar 

  • Pillai DR, Heidemann RM, Kumar P, Shanbhag N, Lanz T, Dittmar MS, Sandner B, Beier CP, Weidner N, Greenlee MW, Schuierer G, Bogdahn U, Schlachetzki F (2011) Comprehensive small animal imaging strategies on a clinical 3 T dedicated head MR-scanner; adapted methods and sequence protocols in CNS pathologies. PLoS One 6:e16091

    Article  PubMed  CAS  Google Scholar 

  • Pittenger MF (2008) Mesenchymal stem cells from adult bone marrow. Methods Mol Biol 449:27–44

    PubMed  CAS  Google Scholar 

  • Sarkar D, Spencer JA, Phillips JA, Zhao W, Schafer S, Spelke DP, Mortensen LJ, Ruiz JP, Vemula PK, Sridharan R, Kumar S, Karnik R, Lin CP, Karp JM (2011a) Engineered cell homing. Blood 118:e184–e191

    Article  PubMed  CAS  Google Scholar 

  • Sarkar D, Zhao W, Gupta A, Loh WL, Karnik R, Karp JM (2011b) Cell surface engineering of mesenchymal stem cells. Methods Mol Biol 698:505–523

    Article  PubMed  CAS  Google Scholar 

  • Savitz SI, Chopp M, Deans R, Carmichael ST, Phinney D, Wechsler L (2011) Stem cell therapy as an emerging paradigm for stroke (STEPS) II. Stroke 42:825–829

    Article  PubMed  Google Scholar 

  • Sehgal V, DelProposto Z, Haacke EM, Tong KA, Wycliffe N, Kido DK, Xu Y, Neelavalli J, Haddar D, Reichenbach JR (2005) Clinical applications of neuroimaging with susceptibility-weighted imaging. J Magn Reson Imaging 22:439–450

    Article  PubMed  Google Scholar 

  • Seminatore C, Polentes J, Ellman D, Kozubenko N, Itier V, Tine S, Tritschler L, Brenot M, Guidou E, Blondeau J, Lhuillier M, Bugi A, Aubry L, Jendelova P, Sykova E, Perrier AL, Finsen B, Onteniente B (2010) The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke 41:153–159

    Article  PubMed  Google Scholar 

  • Shen LH, Li Y, Chen J, Cui Y, Zhang C, Kapke A, Lu M, Savant-Bhonsale S, Chopp M (2007a) One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke. Stroke 38:2150–2156

    Article  PubMed  Google Scholar 

  • Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (2007b) Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6–13

    Article  PubMed  Google Scholar 

  • Shen LH, Li Y, Gao Q, Savant-Bhonsale S, Chopp M (2008) Down-regulation of neurocan expression in reactive astrocytes promotes axonal regeneration and facilitates the neurorestorative effects of bone marrow stromal cells in the ischemic rat brain. Glia 56:1747–1754

    Article  PubMed  Google Scholar 

  • Shichinohe H, Kuroda S, Yano S, Hida K, Iwasaki Y (2007) Role of SDF-1/CXCR4 system in survival and migration of bone marrow stromal cells after transplantation into mice cerebral infarct. Brain Res 1183:138–147

    Article  PubMed  CAS  Google Scholar 

  • Shobha N, Buchan AM, Hill MD (2011) Thrombolysis at 3–4.5 hours after acute ischemic stroke onset–evidence from the Canadian Alteplase for Stroke Effectiveness Study (CASES) registry. Cerebrovasc Dis 31:223–228

    Article  PubMed  Google Scholar 

  • Stroh A, Zimmer C, Gutzeit C, Jakstadt M, Marschinke F, Jung T, Pilgrimm H, Grune T (2004) Iron oxide particles for molecular magnetic resonance imaging cause transient oxidative stress in rat macrophages. Free Radic Biol Med 36:976–984

    Article  PubMed  CAS  Google Scholar 

  • Stroh A, Faber C, Neuberger T, Lorenz P, Sieland K, Jakob PM, Webb A, Pilgrimm H, Schober R, Pohl EE, Zimmer C (2005) In vivo detection limits of magnetically labeled embryonic stem cells in the rat brain using high-field (17.6 T) magnetic resonance imaging. Neuroimage 24:635–645

    Article  PubMed  Google Scholar 

  • Stroh A, Zimmer C, Werner N, Gertz K, Weir K, Kronenberg G, Steinbrink J, Mueller S, Sieland K, Dirnagl U, Nickenig G, Endres M (2006) Tracking of systemically administered mononuclear cells in the ischemic brain by high-field magnetic resonance imaging. Neuroimage 33:886–897

    Article  PubMed  Google Scholar 

  • Stroh A, Boltze J, Sieland K, Hild K, Gutzeit C, Jung T, Kressel J, Hau S, Reich D, Grune T, Zimmer C (2009) Impact of magnetic labeling on human and mouse stem cells and their long-term magnetic resonance tracking in a rat model of Parkinson disease. Mol Imaging 8:166–178

    PubMed  CAS  Google Scholar 

  • Tsai LK, Wang Z, Munasinghe J, Leng Y, Leeds P, Chuang DM (2011) Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model. Stroke 42:2932–2939

    Article  PubMed  Google Scholar 

  • Ukai R, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD (2007) Mesenchymal stem cells derived from peripheral blood protects against ischemia. J Neurotrauma 24:508–520

    Article  PubMed  Google Scholar 

  • Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W (2007) Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 6:215–222

    Article  PubMed  Google Scholar 

  • Wu J, Sun Z, Sun HS, Wu J, Weisel RD, Keating A, Li ZH, Feng ZP, Li RK (2008) Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell Transplant 16:993–1005

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Therapy, Fraunhofer-Institute for Cell Therapy and Immunology, Perlickstraße 1, D-04103, Leipzig, Germany

    Antje Y. Dreyer, Claudia Pösel, Björn Nitzsche & Johannes Boltze

  2. Translational Centre for Regenerative Medicine, University of Leipzig, Philipp-Rosenthal-Straße 55, D-04103, Leipzig, Germany

    Antje Y. Dreyer & Johannes Boltze

  3. Department for Neuroradiology, University of Leipzig, Liebigstraße 20, D-04103, Leipzig, Germany

    Donald Lobsien & Karl-Titus Hoffmann

  4. Department of Chemistry and Mineralogy, Institute of Analytical Chemistry, University of Leipzig, Johannisallee 29, D-04103, Leipzig, Germany

    Matthias Findeisen

  5. Focus Group Translational Neurosciences (FTN), Institute for Microscopic Anatomy and Neurobiology, Johannes Gutenberg-University Mainz, Hanns-Dieter-Hüsch-Weg 19, D-55128, Mainz, Germany

    Albrecht Stroh

Authors
  1. Antje Y. Dreyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donald Lobsien
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Pösel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karl-Titus Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Björn Nitzsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Findeisen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Albrecht Stroh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johannes Boltze
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johannes Boltze .

Editor information

Editors and Affiliations

  1. , Institute of Clinical Medicine, University of Eastern Finland, Kuopio, 70210, Finland

    Jukka Jolkkonen

  2. School of Medicine, Division of MR Research, Johns Hopkins University, N Broadway 733, Baltimore, 21205, Maryland, USA

    Piotr Walczak

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Wien

About this chapter

Cite this chapter

Dreyer, A.Y. et al. (2013). Tracking of Autologous VSOP-Labeled Mesenchymal Stem Cells in the Sheep Brain Using 3.0 T MRI. In: Jolkkonen, J., Walczak, P. (eds) Cell-Based Therapies in Stroke. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1175-8_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-1175-8_8

  • Published:

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-1174-1

  • Online ISBN: 978-3-7091-1175-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation