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Human autologous iPSC–derived dopaminergic progenitors restore motor function in Parkinson’s disease models
Bin Song, … , Jeffrey S. Schweitzer, Kwang-Soo Kim
Bin Song, … , Jeffrey S. Schweitzer, Kwang-Soo Kim
Published November 12, 2019
Citation Information: J Clin Invest. 2020;130(2):904-920. https://doi.org/10.1172/JCI130767.
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Research Article Neuroscience Stem cells

Human autologous iPSC–derived dopaminergic progenitors restore motor function in Parkinson’s disease models

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell–based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, we established a “spotting”-based in vitro differentiation methodology to generate functional and healthy mDA cells in a scalable manner. Third, we developed a chemical method that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restores motor function and reinnervates host brain, while showing no evidence of tumor formation or redistribution of the implanted cells. We propose that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.

Authors

Bin Song, Young Cha, Sanghyeok Ko, Jeha Jeon, Nayeon Lee, Hyemyung Seo, Kyung-Joon Park, In-Hee Lee, Claudia Lopes, Melissa Feitosa, María José Luna, Jin Hyuk Jung, Jisun Kim, Dabin Hwang, Bruce M. Cohen, Martin H. Teicher, Pierre Leblanc, Bob S. Carter, Jeffrey H. Kordower, Vadim Y. Bolshakov, Sek Won Kong, Jeffrey S. Schweitzer, Kwang-Soo Kim

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Figure 6

Molecular, cellular, and physiological characterization of in vitro–differentiated C4 hiPSCs.

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Molecular, cellular, and physiological characterization of in vitro–diff...
(A) Schematic overview of mDA differentiation method based on spotting protocol. Numbers represent concentrations in ng/ml, and those in parentheses show μM. AA, ascorbic acid; β-mer, β-mercaptoethanol; BDNF, brain-derived neurotrophic factor; CHIR, CHIR99021; dbcAMP, dibutyryl cyclic adenosine monophosphate; FGF8, fibroblast growth factor 8; GDNF, glial cell line–derived neurotrophic factor; KSR, knockout serum replacement; LDN, LDN193189; L-Glu, l-glutamine; NEAA, nonessential amino acid; PMN, purmorphamine; QC, quercetin; SB, SB431542; SHH, sonic hedgehog. (B) Heatmap of gene expression of stage-specific neural markers in mDA-differentiated cells. (C) Gradual increase in FOXA2, LMX1A, NURR1, and TH gene expression during differentiation. (D) Immunofluorescence staining of neural precursor marker (NESTIN), mDAP markers (FOXA2/LMX1A/TH), mDAN markers (MAP2, NURR1/TH), and proliferating marker (PAX6/SOX1/KI67) cells in differentiated d28 cells. Scale bars: 100 μm. (E) Percentages of NESTIN+, MAP2+, TH+, and NURR1+ cells among total d28 cells (n = 6). (F) Percentages of FOXA2+, LMXA1+, and FOXA2+LMX1A+cells among total d28 cells (n = 6). (G) Percentages of FOXA2+LMX1A+, NURR1+ cells among TH+ d28 cells (n = 6). (H) Percentages of PAX6+, SOX1+, and PAX6+SOX1+KI67+ cells among total d28 cells (n = 6). (I) HPLC analysis of KCl-induced release of DA and DA metabolites (DOPAC) on d47. Data are presented as mean ± SEM.
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