Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model
Jae-Jin Song, … , C. Justin Lee, Sang-Hun Lee
Jae-Jin Song, … , C. Justin Lee, Sang-Hun Lee
Published December 11, 2017
Citation Information: J Clin Invest. 2018;128(1):463-482. https://doi.org/10.1172/JCI93924.
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Research Article Neuroscience Transplantation

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

Abstract

Transplantation of neural progenitor cells (NPCs) is a potential therapy for treating neurodegenerative disorders, but this approach has faced many challenges and limited success, primarily because of inhospitable host brain environments that interfere with enriched neuron engraftment and function. Astrocytes play neurotrophic roles in the developing and adult brain, making them potential candidates for helping with modification of hostile brain environments. In this study, we examined whether astrocytic function could be utilized to overcome the current limitations of cell-based therapies in a murine model of Parkinson’s disease (PD) that is characterized by dopamine (DA) neuron degeneration in the midbrain. We show here that cografting astrocytes, especially those derived from the midbrain, remarkably enhanced NPC-based cell therapeutic outcomes along with robust DA neuron engraftment in PD rats for at least 6 months after transplantation. We further show that engineering of donor astrocytes with Nurr1 and Foxa2, transcription factors that were recently reported to polarize harmful immunogenic glia into the neuroprotective form, further promoted the neurotrophic actions of grafted astrocytes in the cell therapeutic approach. Collectively, these findings suggest that cografting astrocytes could be a potential strategy for successful cell therapeutic outcomes in neurodegenerative disorders.

Authors

Jae-Jin Song, Sang-Min Oh, Oh-Chan Kwon, Noviana Wulansari, Hyun-Seob Lee, Mi-Yoon Chang, Eunsoo Lee, Woong Sun, Sang-Eun Lee, Sunghoe Chang, Heeyoung An, C. Justin Lee, Sang-Hun Lee

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Figure 2

DA neurons differentiated with astrocytes are more resistant to toxic insult along with increased midbrain-specific factor expressions.

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DA neurons differentiated with astrocytes are more resistant to toxic in...
(A–C) Expression of midbrain-specific markers in the differentiated DA neurons. Expression levels of the midbrain-specific markers in C were determined in individual TH+ DA neurons by measuring MFI using LAS image analysis (Leica). *P < 0.01; #P < 0.01, 1-way ANOVA. n = 9 microscopic fields (B) and n = 32–36 TH+ cells (C). Scale bar: 50 μm. (D–F) Resistance of DA neurons against a toxic stimulus. TH+ DA neurons differentiated in the presence of Ctx- or VM-Ast (Ctx-NPCs as the control) at D12 were exposed to H2O2 (1,000 μM) for 10 hours and viable TH+ cell counts (E) and fiber lengths (F) were measured on the following day. Representative TH+ cell images after H2O2 treatment are shown in D. Scale bar: 100 μm. Insets, enlarged images of the boxed areas (original magnification, ×400). Data in E represent percentage of TH+ cells that survived after the toxin exposure compared with those that were not exposed to toxin (H2O2 = 0 μM). *P < 0.01; #P < 0.01, 1-way ANOVA. n = 3 independent experiments (2–3 culture wells/experiment) (E) and n = 80–90 TH+ cells (F).