Docosahexaenoic Acid Promotes Dopaminergic Differentiation in Induced Pluripotent Stem Cells and Inhibits Teratoma Formation in Rats with Parkinson-Like Pathology

Author:

Chang Yuh-Lih12,Chen Shih-Jen23,Kao Chung-Lan23,Hung Shih-Chieh23,Ding Dah-Ching34,Yu Cheng-Chia56,Chen Yi-Jen78,Ku Hung-Hai5,Lin Chin-Po9,Lee Kun-Hsiung10,Chen Yu-Chih23,Wang Jhi-Joung11,Hsu Chuan-Chih11,Chen Liang-Kung212,Li Hsin-Yang578,Chiou Shih-Hwa123

Affiliation:

1. Institute of Pharmacology, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

2. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

3. Institute of Clinical Medicine, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

4. Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital & Tzu Chi University, Taipei, Taiwan

5. Institute of Anatomy and Cell Biology, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

6. Institute of Oral Biology and Biomaterial Science, Chung-Shan Medical University & Department of Dentistry, Chung Shan Medical University Hospital, Taipei, Taiwan

7. Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

8. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan

9. Brain Research Center, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

10. Division of Biotechnology, Animal Technology Institute Taiwan, Chunan, Miaoli, Taiwan

11. Department of Surgery, Chi-Mei Medical Center & Chia Nan University of Pharmacy & Science, Taipei, Taiwan

12. Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic (DA) neurons in the midbrain. Induced pluripotent stem (iPS) cells have shown potential for differentiation and may become a resource of functional neurons for the treatment of PD. However, teratoma formation is a major concern for transplantation-based therapies. This study examined whether functional neurons could be efficiently generated from iPS cells using a five-step induction procedure combined with docosahexaenoic acid (DHA) treatment. We demonstrated that DHA, a ligand for the RXR/Nurr1 heterodimer, significantly activated expression of the Nurr1 gene and the Nurr1-related pathway in iPS cells. DHA treatment facilitated iPS differentiation into tyrosine hydroxylase (TH)-positive neurons in vitro and in vivo and functionally increased dopamine release in transplanted grafts in PD-like animals. Furthermore, DHA dramatically upregulated the endogenous expression levels of neuroprotective genes ( Bcl-2, Bcl-xl, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor) and protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis in iPS-derived neuronal precursor cells. DHA-treated iPS cells significantly improved the behavior of 6-hydroxydopamine (6-OHDA)-treated PD-like rats compared to control or eicosapentaenoic acid-treated group. Importantly, the in vivo experiment suggests that DHA induces the differentiation of functional dopaminergic precursors and improves the abnormal behavior of 6-OHDA-treated PD-like rats by 4 months after transplantation. Furthermore, we found that DHA treatment in iPS cell-grafted rats significantly downregulated the mRNA expression of embryonic stem cell-specific genes (Oct-4 and c-Myc) in the graft and effectively blocked teratoma formation. Importantly, 3 Tesla-magnetic resonance imaging and ex vivo green fluorescence protein imaging revealed that no teratomas were present in transplanted grafts of DHA-treated iPS-derived DA neurons 4 months after implantation. Therefore, our data suggest that DHA plays a crucial role in iPS differentiation into functional DA neurons and that this approach could provide a novel therapeutic approach for PD treatment.

Publisher

SAGE Publications

Subject

Transplantation,Cell Biology,Biomedical Engineering

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