Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology.

doi:10.3727/096368911X580572

中山醫學大學機構典藏 CSMUIR > 口腔醫學院 > 牙醫學系暨碩士班 > 期刊論文 > Item 310902500/15714

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/15714

Title:	Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology.
Authors:	YL, Chang SJ, Chen CL, Kao SC, Hung DC, Ding CC, Yu YJ, Chen HH, Ku CP, Lin KH, Lee YC, Chen JJ, Wang CC, Hsu LK, Chen HY, Li SH, Chiou
Contributors:	中山醫學大學口腔科學研究所
Keywords:	3T-MRI;Docosahexaenoic acid (DHA);Dopamine;Dopaminergic neurons;Induced pluripotent stem cells (iPS);Parkinson's disease
Date:	2011-06-11
Issue Date:	2016-08-11T02:45:50Z (UTC)
ISSN:	0963-6897
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.
URI:	http://dx.doi.org/10.3727/096368911X580572 https://ir.csmu.edu.tw:8080/ir/handle/310902500/15714
Relation:	Cell Transplant. 2012;21(1):313-32
Appears in Collections:	[牙醫學系暨碩士班] 期刊論文

Files in This Item:

File	Description	Size	Format
index.html		0Kb	HTML	333	View/Open

View Licence

Loading...