Format

Send to

Choose Destination
Cells. 2019 Jun 15;8(6). pii: E595. doi: 10.3390/cells8060595.

Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease.

Yu-Taeger L1,2, Stricker-Shaver J3,4, Arnold K5,6, Bambynek-Dziuk P7,8, Novati A9,10, Singer E11,12, Lourhmati A13, Fabian C14,15, Magg J16,17, Riess O18,19, Schwab M20,21,22,23, Stolzing A24,25, Danielyan L26,27,28, Nguyen HHP29,30,31,32,33.

Author information

1
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. Libo.Yu-Taeger@med.uni-tuebingen.de.
2
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. Libo.Yu-Taeger@med.uni-tuebingen.de.
3
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. janice.strickershaver@gmail.com.
4
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. janice.strickershaver@gmail.com.
5
Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, D-04107 Leipzig, Germany. katrin.arnold@izi.fraunhofer.de.
6
Fraunhofer Institute for Cell Therapy and Immunology (IZI), D-04103 Leipzig, Germany. katrin.arnold@izi.fraunhofer.de.
7
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. Patrycja.Bambynek-Dziuk@med.uni-tuebingen.de.
8
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. Patrycja.Bambynek-Dziuk@med.uni-tuebingen.de.
9
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. Arianna.Novati@med.uni-tuebingen.de.
10
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. Arianna.Novati@med.uni-tuebingen.de.
11
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. Elisabeth.Singer@med.uni-tuebingen.de.
12
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. Elisabeth.Singer@med.uni-tuebingen.de.
13
Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany. alilourhmati@yahoo.de.
14
Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, D-04107 Leipzig, Germany. claire.fabian@izi.fraunhofer.de.
15
Fraunhofer Institute for Cell Therapy and Immunology (IZI), D-04103 Leipzig, Germany. claire.fabian@izi.fraunhofer.de.
16
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. Janine.Magg@med.uni-tuebingen.de.
17
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. Janine.Magg@med.uni-tuebingen.de.
18
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. Olaf.Riess@med.uni-tuebingen.de.
19
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. Olaf.Riess@med.uni-tuebingen.de.
20
Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany. Matthias.Schwab@ikp-stuttgart.de.
21
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany. Matthias.Schwab@ikp-stuttgart.de.
22
Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, 0025 Yerevan, Armenia. Matthias.Schwab@ikp-stuttgart.de.
23
Laboratory of Neuroscience, Yerevan State Medical University, 0025 Yerevan, Armenia. Matthias.Schwab@ikp-stuttgart.de.
24
Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, D-04107 Leipzig, Germany. A.Stolzing@lboro.ac.uk.
25
Centre for Biological Engineering, School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough LE11 3TU, UK. A.Stolzing@lboro.ac.uk.
26
Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany. Lusine.Danielyan@med.uni-tuebingen.de.
27
Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, 0025 Yerevan, Armenia. Lusine.Danielyan@med.uni-tuebingen.de.
28
Laboratory of Neuroscience, Yerevan State Medical University, 0025 Yerevan, Armenia. Lusine.Danielyan@med.uni-tuebingen.de.
29
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany. huu.nguyen-r7w@rub.de.
30
Centre for Rare Diseases (ZSE), University of Tuebingen, D-72076 Tuebingen, Germany. huu.nguyen-r7w@rub.de.
31
Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, 0025 Yerevan, Armenia. huu.nguyen-r7w@rub.de.
32
Department of Human Genetics, Ruhr University of Bochum, D-44801 Bochum, Germany. huu.nguyen-r7w@rub.de.
33
Departments of Medical Chemistry and Biochemistry, Yerevan State Medical University, 0025 Yerevan, Armenia. huu.nguyen-r7w@rub.de.

Abstract

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD. GFP-expressing MSCs derived from bone marrow were intranasally administered to 4-week-old R6/2 HD transgenic mice. MSCs were detected in the olfactory bulb, midbrain and striatum five days post-delivery. Compared to phosphate-buffered saline (PBS)-treated littermates, MSC-treated R6/2 mice showed an increased survival rate and attenuated circadian activity disruption assessed by locomotor activity. MSCs increased the protein expression of DARPP-32 and tyrosine hydroxylase (TH) and downregulated gene expression of inflammatory modulators in the brain 7.5 weeks after INA. While vehicle treated R6/2 mice displayed decreased Iba1 expression and altered microglial morphology in comparison to the wild type littermates, MSCs restored both, Iba1 level and the thickness of microglial processes in the striatum of R6/2 mice. Our results demonstrate significantly ameliorated phenotypes of R6/2 mice after MSCs administration via INA, suggesting this method as an effective delivering route of cells to the brain for HD therapy.

KEYWORDS:

Huntington disease; R6/2 mice; cell therapy; dopamine transmission; intranasal; mesenchymal stem cells; microglia; neuroinflammation

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center