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.
View: Text | PDF
Research Article Neuroscience

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

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

×

Figure 3

Genomic integrity of hiPSC lines generated from skin biopsy of a sporadic PD patient.

Options: View larger image (or click on image) Download as PowerPoint
Genomic integrity of hiPSC lines generated from skin biopsy of a sporadi...
(A) Somatic mutations found in 4 hiPSC lines. Columns show the number of singleton mutations in each hiPSC line (different colors per hiPSC line) and number of unique mutations found in 2 or more hiPSC lines (black columns). Below black columns, hiPSC lines sharing the mutations are indicated by dots connected with edges. Bottom left bars represent total numbers of mutations including both singleton and those found in 2 or more hiPSC lines. C4 had the smallest number of somatic mutations (n = 92), of which 80 were singleton and 12 were found in C4 and the other hiPSC lines. (B) Mutational burdens on coding regions and cancer-associated genes were compared with publicly available data sets. The numbers of nonsynonymous mutations in our hiPSC lines were significantly lower than for hESC lines. On average, the numbers of nonsynonymous mutations in the iPSC lines from the HipSci project (28) are similar to those of our hiPSC lines. Overall, C4 shows the lowest mutation burden (red). For the somatic mutations in cancer-associated genes, no somatic mutation was found in 2 widely used hESC lines (H1 and H9, blue) and C4 hiPSC line (red) (right panel). (C) Distribution of minor allelic fractions (MAFs) of all somatic mutations in the 4 hiPSC lines. The peaks around MAF of 0.5 denote clonal somatic mutations. The second peaks with lower MAFs of 0.1 denote subclonal mutations. For each plot, the density curve with 2 peaks shows the distribution of somatic mutation MAFs. The colors of curves match with those in A for each hiPSC line. Curves with different colors (peaked around MAF of 0.0) indicate somatic mutations detected by the other hiPSC lines.