Rejuvenation Research
Therapeutic Efficacy of Intranasally Delivered Mesenchymal Stem Cells in a Rat Model of Parkinson Disease
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To cite this article:
Lusine Danielyan, Richard Schäfer, Andreas von Ameln-Mayerhofer, Felix Bernhard, Stephan Verleysdonk, Marine Buadze, Ali Lourhmati, Tim Klopfer, Felix Schaumann, Barbara Schmid, Christoph Koehle, Barbara Proksch, Robert Weissert, Holger M. Reichardt, Jens van den Brandt, Gayane H. Buniatian, Matthias Schwab, Christoph H. Gleiter, William H. Frey Ii. Rejuvenation Research. -Not available-, ahead of print. doi:10.1089/rej.2010.1130.
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Online Ahead of Print: February 3, 2011
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Lusine Danielyan,1
Richard Schäfer,2,11
Andreas von Ameln-Mayerhofer,3
Felix Bernhard,1
Stephan Verleysdonk,4,10
Marine Buadze,1
Ali Lourhmati,1
Tim Klopfer,1
Felix Schaumann,1
Barbara Schmid,3
Christoph Koehle,5
Barbara Proksch,1
Robert Weissert,6,13
Holger M. Reichardt,7
Jens van den Brandt,7
Gayane H. Buniatian,1,12
Matthias Schwab,1,8
Christoph H. Gleiter,1 and
William H. Frey Ii9
1Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany.
2Institute of Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany.
3Neuropharmacology, Institute of Neurobiology, University of Tübingen, Tübingen, Germany.
4Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
5Department of Toxicology, Institute of Experimental and Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany.
6Experimental Neuroimmunology Laboratory, Department of Neurology, University of Tübingen, Tübingen, Germany.
7Department of Cellular and Molecular Immunology, University of Göttingen Medical School, Göttingen, Germany.
8Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
9Alzheimer's Research Center at Regions Hospital, HealthPartners Research Foundation, St. Paul, Minnesota.
10German University in Cairo, Al Tagamoa Al Khames, New Cairo City, Egypt.
11Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology Harvard University, Cambridge Maasachusetts.
12Institute of Molecular Biology NAS RA, Yerevan, Armenia.
13Department of Neurology, University of Geneva, Geneva University Hospital, Geneva, Switzerland.
Address correspondence to:
Lusine Danielyan, M.D.
Department of Clinical Pharmacology
University Hospital of Tuebingen
Otfried-Mueller Str. 45
D-72076 Tübingen
Germany
E-mail: lusine.danielyan@med.uni-tuebingen.de
Received: November 2, 2010
Accepted: November 20, 2010
Abstract
Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)–lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1?×?106 MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA–induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5'-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40–110 days after INA of 1?×?106 cells. MSC-INA decreased the concentrations of inflammatory cytokines—interleukin-1ß (IL-1ß), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-? (IFN-?, and granulocyte-macrophage colony-stimulating factor (GM-CSF)—in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application.
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