Mesenchymal Stem Cells Form 3D Clusters Following Intraventricular Transplantation
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.
KeywordsMesenchymal stem cells Canine mesenchymal stem cells Human mesenchymal stem cells Cell clusters CD44 Host versus graft reaction
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).
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.
Compliance with Ethical Standards
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).
- 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 8:315–317CrossRefPubMedGoogle 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 230:78–89CrossRefPubMedGoogle 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:e69795CrossRefPubMedPubMedCentralGoogle 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 50:155–165CrossRefPubMedGoogle 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 34:603–620CrossRefPubMedGoogle 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 19:279–289Google Scholar