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):e93924. https://doi.org/10.1172/JCI93924.
View: Text | PDF
Research Article Neuroscience

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

×

Figure 4

Potential molecules mediating the dopaminotrophic functions of astrocytes.

Options: View larger image (or click on image) Download as PowerPoint
Potential molecules mediating the dopaminotrophic functions of astrocyte...
(A–E) mRNA-seq analyses for the DEGs among VM-Ast, Ctx-Ast, and control Ctx-NPCs. Genes upregulated and/or downregulated by over 2-fold were selected for analysis. (A) Venn diagram summarizing the overlap between DEGs from VM-Ast versus Ctx-NPCs (left circle) and Ctx-Ast versus Ctx-NPCs (right circle). The numbers of genes are indicated in the Venn diagram. To calculate overlap with DEGs, statistical analysis was performed using the χ2 test based on a 2 × 2 table using R version 3.3.2 of the MASS package. (B) GO and KEGG analyses for the 4,445 overlapping genes (common astrocytic genes). Purple bars indicate the number of genes under the designated GO term/KEGG pathway. Yellow bars indicate P values, and negative logs of the P values (bottom) are plotted on the x axis. (C and D) Volcano plot (C) and GO/KEGG analyses (D) for the DEGs between VM-Ast and Ctx-Ast. (E) Heatmap showing fold changes of the selected genes in VM- and Ctx-Ast compared with control Ctx-NPCs (log2 folds, VM-Ast/Ctx-NPC and Ctx-Ast/Ctx-NPC). (F) Expression of important pro- and antiinflammatory and secretory antioxidant genes was further confirmed by qPCR analyses. *P < 0.05, significantly different from control; #P < 0.05, significantly different from Ctx-Ast, 1-way ANOVA. n = 3 PCR reactions.