PMID- 28667374 OWN - NLM STAT- MEDLINE DCOM- 20180829 LR - 20181202 IS - 1573-6830 (Electronic) IS - 0272-4340 (Linking) VI - 38 IP - 3 DP - 2018 Apr TI - Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein. PG - 641-655 LID - 10.1007/s10571-017-0513-1 [doi] AB - 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 x 10(6) 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. FAU - Li, Tan AU - Li T AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. FAU - Liu, Yi AU - Liu Y AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. FAU - Yu, Linjie AU - Yu L AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. FAU - Lao, Jiamin AU - Lao J AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. FAU - Zhang, Meijuan AU - Zhang M AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. AD - Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, People's Republic of China. FAU - Jin, Jiali AU - Jin J AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. AD - Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, People's Republic of China. FAU - Lu, Zhengjuan AU - Lu Z AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. AD - Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, People's Republic of China. FAU - Liu, Zhuo AU - Liu Z AUID- ORCID: 0000-0002-1684-9004 AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. aliceliuzhuo@163.com. AD - Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, People's Republic of China. aliceliuzhuo@163.com. FAU - Xu, Yun AU - Xu Y AD - Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 ZhongShan Road, Nanjing City, 210008, Jiangsu Province, People's Republic of China. AD - Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, People's Republic of China. LA - eng GR - 81200876/National Natural Science Foundation of China/ GR - 81230026/National Natural Science Foundation of China/ GR - 81501028/National Natural Science Foundation of China/ GR - 81300988/National Natural Science Foundation of China/ GR - H201538/science foundation from Jiangsu Provincial Commission of health and family planning/ PT - Journal Article DEP - 20170630 PL - United States TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (HSP70 Heat-Shock Proteins) RN - 0 (Nerve Growth Factors) RN - 0 (Protective Agents) RN - EC 3.4.19.12 (Ataxin-3) RN - EC 3.4.19.12 (Atxn3 protein, mouse) SB - IM MH - Animals MH - Ataxin-3/*metabolism MH - Cell Differentiation/drug effects/physiology MH - Cells, Cultured MH - Cerebellum/drug effects/metabolism MH - HSP70 Heat-Shock Proteins/*metabolism MH - Humans MH - *Mesenchymal Stem Cell Transplantation/methods MH - Mesenchymal Stem Cells/*cytology/drug effects MH - Mice, Transgenic MH - Nerve Growth Factors/metabolism MH - Neurons/drug effects/metabolism MH - Protective Agents/pharmacology MH - Umbilical Cord/cytology/*drug effects OTO - NOTNLM OT - Ataxia OT - HSP70 OT - Human umbilical cord mesenchymal stem cells OT - Neurotrophins OT - Purkinje cells OT - Spinocerebellar ataxia 3 EDAT- 2017/07/02 06:00 MHDA- 2018/08/30 06:00 CRDT- 2017/07/02 06:00 PHST- 2017/03/12 00:00 [received] PHST- 2017/06/17 00:00 [accepted] PHST- 2017/07/02 06:00 [pubmed] PHST- 2018/08/30 06:00 [medline] PHST- 2017/07/02 06:00 [entrez] AID - 10.1007/s10571-017-0513-1 [pii] AID - 10.1007/s10571-017-0513-1 [doi] PST - ppublish SO - Cell Mol Neurobiol. 2018 Apr;38(3):641-655. doi: 10.1007/s10571-017-0513-1. Epub 2017 Jun 30.