Skip to main content

Advertisement

SpringerLink
Log in

Mesenchymal Stem Cells Form 3D Clusters Following Intraventricular Transplantation

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Mesenchymal stem cells (MSCs) are regarded as an immune privileged cell type with numerous regeneration-promoting effects. The in vivo behavior of MSC and underlying mechanisms leading to their regenerative effects are largely unknown. The aims of this study were to comparatively investigate the in vivo behavior of canine (cMSC), human (hMSC), and murine MSC (mMSC) following intra-cerebroventricular transplantation. At 7 days post transplantation (dpt), clusters of cMSC, hMSC, and mMSC were detected within the ventricular system. At 49 dpt, cMSC-transplanted mice showed clusters mostly consisting of extracellular matrix lacking transplanted MSC. Similarly, hMSC-transplanted mice lacked MSC clusters at 49 dpt. Xenogeneic MSC transplantation was associated with a local T lymphocyte-dominated immune reaction at both time points. Interestingly, no associated inflammation was observed following syngeneic mMSC transplantation. In conclusion, transplanted MSC formed intraventricular cell clusters and exhibited a short life span in vivo. Xenogeneically in contrast to syngeneically transplanted MSC triggered a T cell-mediated graft rejection indicating that MSCs are not as immune privileged as previously assumed. However, MSC may mediate their effects by a “hit and run” mechanism and future studies will show whether syngeneically or xenogeneically transplanted MSCs exert better therapeutic effects in animals with CNS disease.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Anderson AJ, Haus DL, Hooshmand MJ, Perez H, Sontag CJ, Cummings BJ (2011) Achieving stable human stem cell engraftment and survival in the CNS: is the future of regenerative medicine immunodeficient? Regen Med 6:367–406

    Article  PubMed  PubMed Central  Google Scholar 

  • Barry FP, Murphy JM (2004) Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol 36:568–584

    Article  PubMed  CAS  Google Scholar 

  • Bernardo ME, Fibbe WE (2013) Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13:392–402

    Article  PubMed  CAS  Google Scholar 

  • Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, Fries JW, Tiemann K, Bohlen H, Hescheler J, Welz A, Bloch W, Jacobsen SE, Fleischmann BK (2007) Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110:1362–1369

    Article  PubMed  CAS  Google Scholar 

  • de Bakker E, Van Ryssen B, De Schauwer C, Meyer E (2013) Canine mesenchymal stem cells: state of the art, perspectives as therapy for dogs and as a model for man. Vet Q 33:225–233

    Article  PubMed  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  PubMed  CAS  Google Scholar 

  • Edamura K, Kuriyama K, Kato K, Nakano R, Teshima K, Asano K, Sato T, Tanaka S (2012) Proliferation capacity, neuronal differentiation potency and microstructures after the differentiation of canine bone marrow stromal cells into neurons. J Vet Med Sci 74:923–927

    Article  PubMed  Google Scholar 

  • Fortier LA, Travis AJ (2011) Stem cells in veterinary medicine. Stem Cell Res Ther 2:9

    Article  PubMed  PubMed Central  Google Scholar 

  • Friedenstein AJ, Piatetzky S II, Petrakova KV (1966) Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 16:381–390

    PubMed  CAS  Google Scholar 

  • Gordon D, Pavlovska G, Uney JB, Wraith DC, Scolding NJ (2010) Human mesenchymal stem cells infiltrate the spinal cord, reduce demyelination, and localize to white matter lesions in experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol 69:1087–1095

    Article  PubMed  Google Scholar 

  • Grigoriadis N, Lourbopoulos A, Lagoudaki R, Frischer JM, Polyzoidou E, Touloumi O, Simeonidou C, Deretzi G, Kountouras J, Spandou E, Kotta K, Karkavelas G, Tascos N, Lassmann H (2011) Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis. Exp Neurol 230:78–89

    Article  PubMed  Google Scholar 

  • Guercio A, Di Bella S, Casella S, Di Marco P, Russo C, Piccione G (2013) Canine mesenchymal stem cells (MSCs): characterization in relation to donor age and adipose tissue-harvesting site. Cell Biol Int 37:789–798

    Article  PubMed  CAS  Google Scholar 

  • Haeger JD, Hambruch N, Dilly M, Froehlich R, Pfarrer C (2011) Formation of bovine placental trophoblast spheroids. Cells Tissues Organs 193:274–284

    Article  PubMed  CAS  Google Scholar 

  • Han SM, Lee HW, Bhang DH, Seo KW, Youn HY (2012) Canine mesenchymal stem cells are effectively labeled with silica nanoparticles and unambiguously visualized in highly autofluorescent tissues. BMC Vet Res 8:145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hansmann F, Herder V, Kalkuhl A, Haist V, Zhang N, Schaudien D, Deschl U, Baumgärtner W, Ulrich R (2012) Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis. Acta Neuropathol 124:127–142

    Article  PubMed  CAS  Google Scholar 

  • Harding J, Roberts RM, Mirochnitchenko O (2013) Large animal models for stem cell therapy. Stem Cell Res Ther 4:23

    Article  PubMed  PubMed Central  Google Scholar 

  • Heinrich F, Jungwirth N, Carlson R, Tipold A, Böer M, Scheibe T, Molnár V, von Dörnberg K, Spitzbarth I, Puff C, Wohlsein P, Baumgärtner W (2015) Immunophenotyping of immune cell populations in the raccoon (Procyon lotor). Vet Immunol Immunopathol 168:140–146

    Article  PubMed  CAS  Google Scholar 

  • Herder V, Hansmann F, Stangel M, Schaudien D, Rohn K, Baumgärtner W, Beineke A (2012) Cuprizone inhibits demyelinating leukomyelitis by reducing immune responses without virus exacerbation in an infectious model of multiple sclerosis. J Neuroimmunol 244:84–93

    Article  PubMed  CAS  Google Scholar 

  • Hernigou P (2015) Bone transplantation and tissue engineering, part IV. Mesenchymal stem cells: history in orthopedic surgery from Cohnheim and Goujon to the Nobel Prize of Yamanaka. Int Orthop 39:807–817

    Article  PubMed  Google Scholar 

  • Hoogduijn MJ, Popp F, Verbeek R, Masoodi M, Nicolaou A, Baan C, Dahlke MH (2010) The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol 10:1496–1500

    Article  PubMed  CAS  Google Scholar 

  • Ingulli E (2010) Mechanism of cellular rejection in transplantation. Pediatr Nephrol 25:61–74

    Article  PubMed  Google Scholar 

  • Jeffery ND, Smith PM, Lakatos A, Ibanez C, Ito D, Franklin RJ (2006) Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy. Spinal Cord 44:584–593

    Article  PubMed  CAS  Google Scholar 

  • Jung DI, Ha J, Kang BT, Kim JW, Quan FS, Lee JH, Woo EJ, Park HM (2009) A comparison of autologous and allogenic bone marrow-derived mesenchymal stem cell transplantation in canine spinal cord injury. J Neurol Sci 285:67–77

    Article  PubMed  Google Scholar 

  • Kang ES, Ha KY, Kim YH (2012) Fate of transplanted bone marrow derived mesenchymal stem cells following spinal cord injury in rats by transplantation routes. J Korean Med Sci 27:586–593

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216

    Article  PubMed  CAS  Google Scholar 

  • Le Blanc K, Mougiakakos D (2012) Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12:383–396

    Article  PubMed  CAS  Google Scholar 

  • Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890–896

    Article  PubMed  CAS  Google Scholar 

  • Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL (2009) Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5:54–63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martinello T, Bronzini I, Maccatrozzo L, Mollo A, Sampaolesi M, Mascarello F, Decaminada M, Patruno M (2011) Canine adipose-derived-mesenchymal stem cells do not lose stem features after a long-term cryopreservation. Res Vet Sci 91:18–24

    Article  PubMed  CAS  Google Scholar 

  • Mimeault M, Hauke R, Batra SK (2007) Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther 82:252–264

    Article  PubMed  CAS  Google Scholar 

  • Nessler J, Benardais K, Gudi V, Hoffmann A, Salinas Tejedor L, Janssen S, Prajeeth CK, Baumgärtner W, Kavelaars A, Heijnen CJ, van Velthoven C, Hansmann F, Skripuletz T, Stangel M (2013) Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination. PLoS One 8:e69795

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reich CM, Raabe O, Wenisch S, Bridger PS, Kramer M, Arnhold S (2012) Isolation, culture and chondrogenic differentiation of canine adipose tissue- and bone marrow-derived mesenchymal stem cells—a comparative study. Vet Res Commun 36:139–148

    Article  PubMed  Google Scholar 

  • Romanov YA, Darevskaya AN, Merzlikina NV, Buravkova LB (2005) Mesenchymal stem cells from human bone marrow and adipose tissue: isolation, characterization, and differentiation potentialities. Bull Exp Biol Med 140:138–143

    Article  PubMed  CAS  Google Scholar 

  • Salinas Tejedor L, Berner G, Jacobsen K, Gudi V, Jungwirth N, Hansmann F, Gingele S, Prajeeth CK, Baumgärtner W, Hoffmann A, Skripuletz T, Stangel M (2015) Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system. Brain Behav Immun 50:155–165

    Article  PubMed  CAS  Google Scholar 

  • Santini MT, Rainaldi G, Indovina PL (2000) Apoptosis, cell adhesion and the extracellular matrix in the three-dimensional growth of multicellular tumor spheroids. Crit Rev Oncol Hematol 36:75–87

    Article  PubMed  CAS  Google Scholar 

  • Screven R, Kenyon E, Myers MJ, Yancy HF, Skasko M, Boxer L, Bigley EC 3rd, Borjesson DL, Zhu M (2014) Immunophenotype and gene expression profile of mesenchymal stem cells derived from canine adipose tissue and bone marrow. Vet Immunol Immunopathol 161:21–31

    Article  PubMed  CAS  Google Scholar 

  • Singer NG, Caplan AI (2011) Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol 6:457–478

    Article  PubMed  CAS  Google Scholar 

  • Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    Article  PubMed  Google Scholar 

  • Spitzbarth I, Baumgärtner W, Beineke A (2012) The role of pro- and anti-inflammatory cytokines in the pathogenesis of spontaneous canine CNS diseases. Vet Immunol Immunopathol 147:6–24

    Article  PubMed  CAS  Google Scholar 

  • Stein VM, Czub M, Hansen R, Leibold W, Moore PF, Zurbriggen A, Tipold A (2004) Characterization of canine microglial cells isolated ex vivo. Vet Immunol Immunopathol 99:73–85

    Article  PubMed  CAS  Google Scholar 

  • Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736

    Article  PubMed  CAS  Google Scholar 

  • Ulrich R, Seeliger F, Kreutzer M, Germann PG, Baumgärtner W (2008) Limited remyelination in Theiler’s murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cells. Neuropathol Appl Neurobiol 34:603–620

    Article  PubMed  CAS  Google Scholar 

  • van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2010) Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res 68:419–422

    Article  PubMed  Google Scholar 

  • Vieira NM, Brandalise V, Zucconi E, Secco M, Strauss BE, Zatz M (2010). Isolation, characterization, and differentiation potential of canine adipose-derived stem cells. Cell Transplant 19:279–289

  • von Bahr L, Batsis I, Moll G, Hagg M, Szakos A, Sundberg B, Uzunel M, Ringden O, Le Blanc K (2012) Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 30:1575–1578

    Article  CAS  Google Scholar 

  • Weinger JG, Weist BM, Plaisted WC, Klaus SM, Walsh CM, Lane TE (2012) MHC mismatch results in neural progenitor cell rejection following spinal cord transplantation in a model of viral-induced demyelination. Stem Cells 30:2584–2595

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Whitworth DJ, Banks TA (2014) Stem cell therapies for treating osteoarthritis: prescient or premature? Vet J 202:416–424

    Article  PubMed  Google Scholar 

  • Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Caroline Schütz, Petra Grünig, Kerstin Schöne, Kerstin Rohn, Regina Carlson, Danuta Waschke, and Bettina Buck for excellent technical assistance. The authors also thank PD Dr. Manuela Gernert, Department of Pharmacology, University of Veterinary Medicine, Hannover, Germany, and Alexander Klein, Department of Neuroanatomy, Medical School Hannover, Germany, for scientific advice. Parts of the data were published in the thesis of Nicole Jungwirth (Deutsche Veterinärmedizinische Gesellschaft, 2016).

Funding

W. Baumgärtner, M. Stangel, and A. Tipold were supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Forschergruppe 1103, BA 815/14-1, STA 518/4-1, TI 309/4-2). This study was in part supported by the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, Germany.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hanover, Germany

    Nicole Jungwirth, Wen Jin, Wolfgang Baumgärtner & Florian Hansmann

  2. Center for Systems Neuroscience, Hannover, Germany

    Nicole Jungwirth, Laura Salinas Tejedor, Wen Jin, Viktoria Gudi, Andrea Tipold, Martin Stangel, Wolfgang Baumgärtner & Florian Hansmann

  3. Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany

    Laura Salinas Tejedor, Viktoria Gudi, Thomas Skripuletz & Martin Stangel

  4. Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany

    Veronika Maria Stein & Andrea Tipold

  5. Department of Orthopaedic Surgery, Hannover Medical School, Hannover, Germany

    Andrea Hoffmann

Authors
  1. Nicole Jungwirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Salinas Tejedor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viktoria Gudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Skripuletz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Veronika Maria Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrea Tipold
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Martin Stangel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wolfgang Baumgärtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Florian Hansmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolfgang Baumgärtner.

Ethics declarations

Human bone marrow-derived mesenchymal stem cells (hMSCs) were isolated from a healthy, female donor after consent of the ethics committee of Hannover Medical School. Animal experiments were conducted in accordance with the German Animal Welfare Law and all experiments were approved by the local authorities (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit (LAVES), Oldenburg, Germany, permission numbers: 33.12-42502-04-13/1071 and 33.9-42502-05-13A302; Landesamt für Natur, Umwelt und Verbraucherschutz (LANUV), Recklinghausen, Germany, permission number: 501/A80).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jungwirth, N., Salinas Tejedor, L., Jin, W. et al. Mesenchymal Stem Cells Form 3D Clusters Following Intraventricular Transplantation. J Mol Neurosci 65, 60–73 (2018). https://doi.org/10.1007/s12031-018-1070-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-018-1070-x

Keywords

Search

Navigation