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

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. INTRODUCTIONand psychiatric therapies (29). A recent study demonstrated that DHA protected against dendritic pathology Parkinson's disease (PD) is characterized by the proand behavioral deficits and increased the antiapoptotic gressive loss of a specific population of dopaminergic BCL2-associated agonist of cell death (BAD) phosphor-(DA) neurons in the brain, which leads to debilitating ylation associated with protection against Alzheimer's impairments in the control of movement and eventual disease (5). Furthermore, DHA has been used to prevent death (6,31,40). As PD results from the loss of DA neudecreases of DA and serotoninergic neurotransmitters in rons, the prospect of utilizing cell replacement therapies the frontal cortex of piglets fed linoleic acid-deficient for th...

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“…Earlier studies have described the positive influence of DHA on BDNF expression in vitro in induced pluripotent stem cells [89], and in the CNS [90][91][92]. Similarly to IL-6, the lowest concentrations of EPA resulted in an increase in BDNF levels that disappeared at higher concentrations.…”

Nurr1‐Based Therapies for Parkinson's Disease

“…Thus, we propose that it may be an alternative way to facilitate Nurr1 functions through activating or increasing those modulators. Inspiringly, RXR ligands, such as docosahexaenoic acid, bexarotene, LG100268 and XCT0139508 have been demonstrated to protect DA neurons through interaction with Nurr1/RXR heterodimers [87, 90, 91]. Although the biological functions of bexarotene still remains to be defined, one recent study has revealed that bexarotene might have the capacity to rescue the disrupted GDNF signaling and regulate oxidative phosphorylation and Nurr1-related genes [92].…”

Induced Pluripotent Stem Cells Without c-Myc Ameliorate Retinal Oxidative Damage via Paracrine Effects and Reduced Oxidative Stress in Rats

“…40 Our previous study demonstrated that suppression of c-Myc expression effectively blocked teratoma formation in rats transplanted with docosahexaenoic-acid-treated iPSCs 4 months after transplantation. 41 Therefore, exclusion of c-Myc would be a feasible way to reduce the incidence of tumor formation. In the present study, no tumor formation was observed in the recipients of non-c-myc iPSCs over 6 months.…”