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Genome Institute of Singapore

Cell Stem Cell, Published: July 28, 2016 | DOI: http://dx.doi.org/10.1016/j.stem.2016.07.005 Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons

Abstract

Junghyun Jo,¹ Yixin Xiao,^2,3 Alfred Xuyang Sun,^1,4 Engin Cukuroglu,¹ Hoang-Dai Tran,^1,5 Jonathan Go¨ ke,¹ Zi Ying Tan,^1,6 Tzuen Yih Saw,¹ Cheng-Peow Tan,¹ Hidayat Lokman,² Younghwan Lee,² Donghoon Kim,⁷ Han Seok Ko,⁷ Seong-Oh Kim,⁸ Jae Hyeon Park,⁸ Nam-Joon Cho,^8,9 Thomas M. Hyde,^10,11,12 Joel E. Kleinman,^10,11 Joo Heon Shin,¹⁰ Daniel R. Weinberger,^{10,11,12,13,14} Eng King Tan,⁴ Hyunsoo Shawn Je,^2,3,* and Huck-Hui Ng^1,5,6,15,*

¹Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
²Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
³Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
⁴National Neuroscience Institute, 20 College Road, Singapore 169856, Singapore
⁵Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
⁶Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore
⁷Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
⁸School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore
⁹KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Korea
¹⁰The Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA
¹¹Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
¹²Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
¹³Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
¹⁴McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
¹⁵School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798, Singapore

*Correspondence: Hyunsoo Shawn Je, Huck-Hui Ng

Summary
Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain. Importantly, we detected electrically active and functionally mature mDA neurons and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using 2D methods or MLOs generated from mouse embryonic stem cells, our human MLOs produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a tractable in vitro system to study the human midbrain and its related diseases.

논문정보

형식Research article
게재일2016년 07월 (BRIC 등록일 2016-08-01)
연구진국내+국외 연구진
분야 의약학 > 신경의학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2018-12-07)

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