Abstract
Spinocerebellar ataxia 3 (SCA3), which is a progressive neurodegenerative disease, is currently incurable. Emerging studies have reported that human umbilical cord mesenchymal stem cells (HUC-MSCs) transplantation could be a promising therapeutic strategy for cerebellar ataxias. However, few studies have evaluated the effects of HUC-MSCs on SCA3 transgenic mouse. Thus, we investigated the effects of HUC-MSCs on SCA3 mice and the underlying mechanisms in this study. SCA3 transgenic mice received systematic administration of 2 × 106 HUC-MSCs once per week for 12 continuous weeks. Motor coordination was measured blindly by open field tests and footprint tests. Immunohistochemistry and Nissl staining were applied to detect neuropathological alternations. Neurotrophic factors in the cerebellum were assessed by ELISA. We used western blotting to detect the alternations of heat shock protein 70 (HSP70), IGF-1, mutant ataxin-3, and apoptosis-associated proteins. Tunel staining was also used to detect apoptosis of affected cells. The distribution and differentiation of HUC-MSCs were determined by immunofluorescence. Our results exhibited that HUC-MSCs transplantation significantly alleviated motor impairments, corresponding to a reduction of cerebellar atrophy, preservation of neurons, decreased expression of mutant ataxin-3, and increased expression of HSP70. Implanted HUC-MSCs were mainly distributed in the cerebellum and pons with no obvious differentiation, and the expressions of IGF-1, VEGF, and NGF in the cerebellum were significantly elevated. Furthermore, with the use of HSP70 analogy quercetin injection, it demonstrated that HSP70 is involved in mutant ataxin-3 reduction. These results showed that HUC-MSCs implantation is a potential treatment for SCA3, likely through upregulating the IGF-1/HSP70 pathway and subsequently inhibiting mutant ataxin-3 toxicity.
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Abbreviations
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- HLA:
-
Human leukocyte antigen
- HSP70:
-
Heat protein 70
- HUC-MSCs:
-
Human umbilical cord mesenchymal stem cells
- IGL:
-
Internal granular layer
- ML:
-
Molecular layer
- MSCs:
-
Mesenchymal stem cells
- PCL:
-
Purkinje cell layer
- PFA:
-
Paraformaldehyde
- P3:
-
Passage three
- SCA3:
-
Spinocerebellar ataxia 3
- WT:
-
Wild type
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Acknowledgements
We express our sincere appreciation to the patients who provided umbilical cord in the research. We thank the department of Obstetrics and Gynecology of Drum Tower Hospital of Nanjing University Medical School for material support.
Funding
This work was funded by the National Nature Science Foundation of China (81200876, 81230026, 81300988 and 81501028) and the Science Foundation from Jiangsu Provincial Commission of Health and Family Planning (H201538).
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TL designed experiments, contributed ideas, and revised manuscript. YL, LY, and JL contributed to the experiments performance and the collection/assembly of data. MZ, YX, JJ, and ZL contributed to data analysis, results interpretation, and manuscript editing. ZL conceived the experiments, developed the project, contributed ideas, and wrote the manuscript. All authors read and approved the final manuscript.
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Li, T., Liu, Y., Yu, L. et al. Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein. Cell Mol Neurobiol 38, 641–655 (2018). https://doi.org/10.1007/s10571-017-0513-1
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DOI: https://doi.org/10.1007/s10571-017-0513-1