Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease
Libo Yu-Taeger,
Janice Stricker-Shaver,
Katrin Arnold,
Patrycja Bambynek-Dziuk,
Arianna Novati,
Elisabeth Singer,
Ali Lourhmati,
Claire Fabian,
Janine Magg,
Olaf Riess,
Matthias Schwab,
Alexandra Stolzing,
Lusine Danielyan,
Hoa Huu Phuc Nguyen
Affiliations
Libo Yu-Taeger
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Janice Stricker-Shaver
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Katrin Arnold
Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, D-04107 Leipzig, Germany
Patrycja Bambynek-Dziuk
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Arianna Novati
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Elisabeth Singer
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Ali Lourhmati
Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany
Claire Fabian
Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, D-04107 Leipzig, Germany
Janine Magg
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Olaf Riess
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
Matthias Schwab
Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany
Alexandra Stolzing
Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, D-04107 Leipzig, Germany
Lusine Danielyan
Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany
Hoa Huu Phuc Nguyen
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
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.
