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Human iPSCs derived astrocytes rescue rotenone-induced mitochondrial dysfunction and dopaminergic neurodegeneration in vitro by donating functional mitochondria.
Cheng, Xiao-Yu; Biswas, Sangita; Li, Juan; Mao, Cheng-Jie; Chechneva, Olga; Chen, Jing; Li, Kai; Li, Jiao; Zhang, Jin-Ru; Liu, Chun-Feng; Deng, Wen-Bin.
Affiliation
  • Cheng XY; Department of Neurology and Suzhou Clinical Research of Neurological Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
  • Biswas S; Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817, USA.
  • Li J; Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817, USA.
  • Mao CJ; Shriners Hospital for Children of Northern California, Sacramento, CA, 95817, USA.
  • Chechneva O; School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
  • Chen J; Key Laboratory of Hui Medicine Modernization, Ministry of Education, Yinchuan, 750004, China.
  • Li K; Department of Neurology and Suzhou Clinical Research of Neurological Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
  • Li J; Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817, USA.
  • Zhang JR; Department of Neurology and Suzhou Clinical Research of Neurological Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
  • Liu CF; Department of Neurology and Suzhou Clinical Research of Neurological Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
  • Deng WB; Department of Neurology and Suzhou Clinical Research of Neurological Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Transl Neurodegener ; 9(1): 13, 2020 04 24.
Article in En | MEDLINE | ID: mdl-32345341
BACKGROUND: Parkinson's disease (PD) is one of the neurodegeneration diseases characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra region of the brain. Substantial evidence indicates that at the cellular level mitochondrial dysfunction is a key factor leading to pathological features such as neuronal death and accumulation of misfolded α-synuclein aggregations. Autologous transplantation of healthy purified mitochondria has shown to attenuate phenotypes in vitro and in vivo models of PD. However, there are significant technical difficulties in obtaining large amounts of purified mitochondria with normal function. In addition, the half-life of mitochondria varies between days to a few weeks. Thus, identifying a continuous source of healthy mitochondria via intercellular mitochondrial transfer is an attractive option for therapeutic purposes. In this study, we asked whether iPSCs derived astrocytes can serve as a donor to provide functional mitochondria and rescue injured DA neurons after rotenone exposure in an in vitro model of PD. METHODS: We generated DA neurons and astrocytes from human iPSCs and hESCs. We established an astroglial-neuronal co-culture system to investigate the intercellular mitochondrial transfer, as well as the neuroprotective effect of mitochondrial transfer. We employed immunocytochemistry and FACS analysis to track mitochondria. RESULTS: We showed evidence that iPSCs-derived astrocytes or astrocytic conditioned media (ACM) can rescue DA neurons degeneration via intercellular mitochondrial transfer in a rotenone induced in vitro PD model. Specifically, we showed that iPSCs-derived astrocytes from health spontaneously release functional mitochondria into the media. Mito-Tracker Green tagged astrocytic mitochondria were detected in the ACM and were shown to be internalized by the injured neurons via a phospho-p38 depended pathway. Transferred mitochondria were able to significantly reverse DA neurodegeneration and axonal pruning following exposure to rotenone. When rotenone injured neurons were cultured in presence of ACM depleted of mitochondria (by ultrafiltration), the neuroprotective effects were abolished. CONCLUSIONS: Our studies provide the proof of principle that iPSCs-derived astrocytes can act as mitochondria donor to the injured DA neurons and attenuate pathology. Using iPSCs derived astrocytes as a donor can provide a novel strategy that can be further developed for cellular therapy for PD.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rotenone / Astrocytes / Induced Pluripotent Stem Cells / Dopaminergic Neurons / Insecticides / Mitochondria Type of study: Prognostic_studies Limits: Humans Language: En Journal: Transl Neurodegener Year: 2020 Document type: Article Affiliation country: China Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rotenone / Astrocytes / Induced Pluripotent Stem Cells / Dopaminergic Neurons / Insecticides / Mitochondria Type of study: Prognostic_studies Limits: Humans Language: En Journal: Transl Neurodegener Year: 2020 Document type: Article Affiliation country: China Country of publication: United kingdom