한빛사 논문
Bin Song,1,2 Young Cha,1,2 Sanghyeok Ko,1,2 Jeha Jeon,1,2 Nayeon Lee,1,2 Hyemyung Seo,1,2,3 Kyung-Joon Park,1 In-Hee Lee,4,5 Claudia Lopes,1,2 Melissa Feitosa,1,2 María José Luna,1,2 Jin Hyuk Jung,1,2 Jisun Kim,1,2,3 Dabin Hwang,1,2 Bruce M. Cohen,1 Martin H. Teicher,1 Pierre Leblanc,1,2 Bob S. Carter,6 Jeffrey H. Kordower,7 Vadim Y. Bolshakov,1 Sek Won Kong,4,5 Jeffrey S. Schweitzer,6,* and Kwang-Soo Kim1,2,*
1 Department of Psychiatry and 2 Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA. 3 Department of Molecular and Life Sciences, Hanyang University, Ansan, Korea. 4 Department of Pediatrics, 5 Computational Health Informatics Program, Boston Children’s Hospital, and 6 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7 Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
Authorship note: BS, YC, SK, JJ, NL, and HS contributed equally to this work.
*Address correspondence to: Kwang-Soo Kim, Molecular Neurobiology Lab, Room 216, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA. Or to: Jeffrey S. Schweitzer, Department of Neurosurgery, Massachusetts General Hospital, 15 Parkman Street Wang 745, Boston, Massachusetts 02114, USA.
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 produced 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.
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