한빛사 논문
Seung Won Kima,b,c,1, Hye-Ji Wooa,b,c,1, Eun Hee Kima, Hyung Sun Kimd, Hanna Suhe, Soo-hyun Kima,b,c, Jae-Jin Songa,b, Noviana Wulansaria,b, Minji Kanga,b,c, Se-Young Choif, Su Jeong Choif, Won Hyuk Jangg, Jungbin Leeh, Ki Hean Kimg,h, Wongyoung Leei,j, Sung Hyun Kimi,j, Jinhee Yangk, Jangbeen Kyungk, Hyun-Seob Leel, Sang Myun Parkm, Mi-Yoon Changa,b,*, Sang-Hun Leea,b,c,*
aDepartment of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Republic of Korea
bHanyang Biomedical Research Institute, Hanyang University, Seoul, Republic of Korea
cGraduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
dGeneral Tox. Research Center, 30 Baekhak1-gil, Jeongeup, Jeollabuk-do, 56212, Republic of Korea
eMinipig Model Research Group, Animal Model Research Center, 30 Baekhak1-gil, Jeongeup, Jeollabuk-do, 56212, Republic of Korea
fDepartment of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul, 110-749, Republic of Korea
gDivision of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk, 37673, Republic of Korea
hDepartment of Mechanical Engineering, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-gu, Pohang, Gyeongbuk, 37673, Republic of Korea
iDepartment of Neuroscience, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
jDepartment of Physiology, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
kChong Kun Dang Research Institute, 315-20, Dongbaekjukjeon-daero, Gheung-gu, Yongin-si, Gyeonggi-do, 16995, Republic of Korea
lGenomic Core Facility, Transdisciplinary Research & Collaboration Division, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
mDepartment of Pharmacology, Ajou University School of Medicine, Suwon, Republic of Korea
1Contributed equally.
*Corresponding author
Abstract
Successful clinical translation of stem cell-based therapy largely relies on the scalable and reproducible preparation of donor cells with potent therapeutic capacities. In this study, midbrain organoids were yielded from human pluripotent stem cells (hPSCs) to prepare cells for Parkinson’s disease (PD) therapy. Neural stem/precursor cells (NSCs) isolated from midbrain organoids (Og-NSCs) expanded stably and differentiated into midbrain-type dopamine(mDA) neurons, and an unprecedentedly high proportion expressed midbrain-specific factors, with relatively low cell line and batch-to-batch variations. Single cell transcriptome analysis followed by in vitro assays indicated that the majority of cells in the Og-NSC cultures are ventral midbrain (VM)-patterned with low levels of cellular senescence/aging and mitochondrial stress, compared to those derived from 2D-culture environments. Notably, in contrast to current methods yielding mDA neurons without astrocyte differentiation, mDA neurons that differentiated from Og-NSCs were interspersed with astrocytes as in the physiologic brain environment. Thus, the Og-NSC-derived mDA neurons exhibited improved synaptic maturity, functionality, resistance to toxic insults, and faithful expressions of the midbrain-specific factors, in vitro and in vivo long after transplantation. Consequently, Og-NSC transplantation yielded potent therapeutic outcomes that are reproducible in PD model animals. Collectively, our observations demonstrate that the organoid-based method may satisfy the demands needed in the clinical setting of PD cell therapy.
Keywords : parkinson's disease, midbrain organoid, neural stem cell, dopaminergic neuron, astrocyte, cell therapy
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