Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease

Oh, Seung-Yong; Chang, Mi Yoon; Song, Jae J.; Rhee, Yong; Joe, Eun Hye; Lee, Hyun‐Seob; Yi, Sang Hoon

doi:10.15252/emmm.201506162

Cited by 25 publications

(35 citation statements)

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“…As these midbrain markers play critical roles in DA phenotype maintenance, survival, and function (36)(37)(38)(39), their expression is critical in the preparation of mDA neurons for therapeutic purposes. However, we and others have recently shown that the expression of midbrain-specific markers in mDA neurons is largely affected by in vitro and in vivo environments and thus easily lost during passages, long after differentiation in vitro and after transplantation in vivo (16,40,41). Indeed, expression of Foxa2, Nurr1, and Lmx1a was detected only in 64%, 44%, and 46% of TH + cells at day 12 of differentiation, respectively ( Figure 2, A and B).…”

Section: Resultsmentioning

confidence: 83%

“…66). In this study, we carried out further systematic and comparative analyses both in vitro and in vivo after transplantation to test the dopaminotrophic functions of cultured VM-Ast in comparison with astrocytes cultured from the nondopaminergic region of the Ctx and the effects of priming the VM-Ast with Nurr1+Foxa2, which has been reported to potentiate the neurotrophic functions of glia (16). In the niche established by the VM-Ast, grafted NPCs efficiently differentiated into morphologically, synaptically, and functionally mature mDA neurons and the differentiated mDA neuronal cells survived for long periods after transplantation while maintaining expression of midbrain-specific markers.…”

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

“…The expression of midbrain-specific factors such as Nurr1 and Foxa2 is a critical indicator for successful mDA neuron engraftment (49), as the expression of these genes is required for mDA neuron survival, function, and phenotype maintenance (36)(37)(38)(39). Considering that the expression of midbrain factors is easily lost in stressful conditions (16,40,41), sustained expression of midbrain markers in the presence of astrocytes is likely to be attained by the observed astrocyte actions that change the hostile inflammatory host brain milieu into a neurotrophic environment. Mechanisms underlying the astrocyte-mediated dopaminotrophic niche included secretion of the reported neurotrophic factors as well as other cytokines, such as SHH and FGF8, which had much greater levels of expression in cultured VM-Ast than in Ctx-Ast.…”

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

“…Only a slight but significant increase in the TH + fiber lengths was detected in the N+F-VM-Ast-cografted groups compared with those cografted with the control-VM-Ast ( Figure 9J). Surprisingly, the midbrain-specific markers Nurr1 and Foxa2, expression of which is easily lost in donor cells after transplantation (16,40,41), were faithfully colocalized in TH + DA neurons in the grafts generated by astrocyte cotransplantation, especially by cografting with N+F-VM-Ast, even 6 months after transplantation (Supplemental Figure 6, A-C). TH + DA neuronal cells in the grafts were surrounded by GFAP + astrocytes (probably both transplanted and endogenous) (Supplemental Figure 6D) and Iba1 + microglia (endogenous) (Supplemental Figure 6E).…”

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

“…Behavior tests Animal behaviors were assessed using amphetamine-induced rotation, step adjustment, and cylinder tests as previously described (16).…”

Section: Nurr1+foxa2 Transductionmentioning

confidence: 99%

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Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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In this study, we have attempted to exploit the neurotrophic actions of astrocytes and Nurr1+Foxa2 functions in this cell type to improve the therapeutic outcomes of NPC transplantation using an animal model of PD. Our in vitro assays using a coculture system and conditioned media treatment revealed that astrocytes, especially those cultured from the ventral midbrain (VM), where HNF3β) is a potent cofactor that synergizes the Nurr1-mediated antiinflammatory roles in glia (16). Furthermore, forced coexpression of Nurr1 and Foxa2 (Nurr1+Foxa2) in glia promotes the synthesis and release of various neurotrophic factors, indicating that engineering of Nurr1 and Foxa2 in glia could become a powerful strategy for treating CNS disorders. Representative images of TH + DA neurons differentiated from VM-NPCs in the presence of Ctx-NPCs (control), Ctx-Ast, or VM-Ast. Scale bar: 100 μm. Insets, enlarged images of the boxed areas (original magnification, ×400). (C) DA neuronal yields at differentiation day 6 (D6). (D-H) Morphometric measurement of DA neuron maturity assessed by neurite outgrowth lengths (D), soma size (E), and by the Sholl test (F and G). In the Sholl analysis, the total number of neurite crossings was counted in each circle with the radius increasing in steps of 15 μm (F). The critical value (G) is the radius at which there was a maximum number of neurite crossings. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast, 1-way ANOVA. n = 3-5 wells (C) and 100 (D and E) and 25-30 (F and G) TH + cells in each group.(H) Representative TH + neuronal morphologies reconstructed in 3D by Neurolucida. (I-L) Synaptic densities on TH + fibers. (I) Representative confocal images of synapsin + TH + fibers. Scale bar: 25 μm. Puncta positive for the synaptic vesicle-specific markers SV2 (J), synapsin (K), and bassoon (L) on TH + fibers were counted. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast. n = 20 TH + fibers for each group. (M) Presynaptic DA release. n = 3 independent cultures. DA levels were measured in the media conditioned in the differentiated cultures for 24 hours (D13-D15) and in cultures evoked by KCl-mediated depolarization for 30 minutes. *P < 0.05; # P < 0.05, 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 6 5 jci.org Volume 128 Number 1 January 2018 (Supplemental Figure 1B; supplemental material available online with this article; https://doi.org/10.1172/JCI93924DS1), immunocytochemical analyses revealed that major cell populations in the Ctx-and VM-astroglial cultures at day in vitro (DIV) 14 were positive for GFAP (85% and 82%), CD44 (79% and 76 %), GLT-1 (58% and 71 %), and GLAST protein (71% and 77%), respectively (Supplemental Figure 1A), except S100β (20% and 32%), a soluble protein associated with harmful reactivation of astrocytes (22). A few (0.24% ± 0.35% in Ctx-Ast and 0.43% ± 0.39% in VM-Ast, where Ast indicates astrocytes) and none of the cells in these c...

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Section: Resultsmentioning

confidence: 83%

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

“…Behavior tests Animal behaviors were assessed using amphetamine-induced rotation, step adjustment, and cylinder tests as previously described (16).…”

Section: Nurr1+foxa2 Transductionmentioning

confidence: 99%

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Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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Ultrasound‐triggered effects of the microbubbles coupled to GDNF‐ and Nurr1‐loaded PEGylated liposomes in a rat model of Parkinson's disease

Yue

Gao

Wang³

et al. 2018

J of Cellular Biochemistry

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The purpose of this study was to investigate ultrasound-triggered effects of the glial cell line-derived neurotrophic factor (GDNF) + nuclear receptor-related factor 1 (Nurr1)-polyethylene glycol (PEG)ylated liposomes-coupled microbubbles (PLs-GDNF + Nurr1-MBs) on behavioral impairment and neuron loss in a rat model of Parkinson's disease (PD). The unloaded PEGylated liposomes-coupled microbubbles (PLs-MBs) were characterized for zeta potential, particle size, and concentration. 6-hydroxydopamine (6-OHDA) was used to establish the PD rat model. Rotational, climbing pole, and suspension tests were used to detect behavioral impairment. The immunohistochemical staining of tyrosine hydroxylase (TH) and dopamine transporter (DAT) was used to assess the neuron loss. Western blot and quantitative real-time PCR (qRT-PCR) analysis were used to measure the expression levels of GDNF and Nurr1. The particle size of PLs-MBs was gradually increased, while the concentration and absolute zeta potential were gradually decreased as the time prolongs. 6-OHDA increased amphetamine-induced rotations and loss of dopaminergic neurons as compared to sham group. Interestingly, PLs-GDNF-MBs or PLs-Nurr1-MBs decreased rotations and increased the TH and DAT immunoreactivity. Combined of both genes resulted in a robust reduction in the rotations and a greater increase of the dopaminergic neurons. The delivery of PLs-GDNF + Nurr1-MBs into the brains using magnetic resonance imaging (MRI)-guided focused ultrasound may be more efficacious for the treatment of PD than the single treatment.

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Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons

et al. 2019

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Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease

Cited by 25 publications

References 0 publications

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Ultrasound‐triggered effects of the microbubbles coupled to GDNF‐ and Nurr1‐loaded PEGylated liposomes in a rat model of Parkinson's disease

Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons

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