Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein.

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.

• Authors: Tan Li, Yi Liu, Linjie Yu, Jiamin Lao, Meijuan Zhang, Jiali Jin, Zhengjuan Lu, Zhuo Liu, Yun Xu
• Journal: Cellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 38 Issue 3 Pg. 641-655 (Apr 2018) ISSN: 1573-6830 [Electronic] United States
• PMID: 28667374 (Publication Type: Journal Article)

Chemical References

• HSP70 Heat-Shock Proteins
• Nerve Growth Factors
• Protective Agents
• Ataxin-3
• Atxn3 protein, mouse

Topics

• Animals
• Ataxin-3 (metabolism)
• Cell Differentiation (drug effects, physiology)
• Cells, Cultured
• Cerebellum (drug effects, metabolism)
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Mesenchymal Stem Cell Transplantation (methods)
• Mesenchymal Stem Cells (cytology, drug effects)
• Mice, Transgenic
• Nerve Growth Factors (metabolism)
• Neurons (drug effects, metabolism)
• Protective Agents (pharmacology)
• Umbilical Cord (cytology, drug effects)