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

Yuh Lih Chang, Shih Jen Chen, Chung Lan Kao, Shih Chieh Hung, Dah Ching Ding, Cheng Chia Yu, Yi Jen Chen, Hung Hai Ku, Chin Po Lin, Kun Hsiung Lee, Yu Chih Chen, Jhi Joung Wang, Chuan Chih Hsu, Liang Kung Chen, Hsin Yang Li, Shih Hwa Chiou

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33 Citations (Scopus)

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-OHDAtreated 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.

Original languageEnglish
Pages (from-to)313-332
Number of pages20
JournalCell Transplantation
Volume21
Issue number1
DOIs
Publication statusPublished - 2012
Externally publishedYes

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Keywords

  • 3T-MRI
  • Docosahexaenoic acid (DHA)
  • Dopamine
  • Dopaminergic neurons
  • Induced pluripotent stem cells (iPS)
  • Parkinson's disease

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation
  • Biomedical Engineering

Cite this

Chang, Y. L., Chen, S. J., Kao, C. L., Hung, S. C., Ding, D. C., Yu, C. C., Chen, Y. J., Ku, H. H., Lin, C. P., Lee, K. H., Chen, Y. C., Wang, J. J., Hsu, C. C., Chen, L. K., Li, H. Y., & Chiou, S. H. (2012). Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology. Cell Transplantation, 21(1), 313-332. https://doi.org/10.3727/096368911X580572