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Cell Stem Cell. 2016 Aug 4;19(2):248-257. doi: 10.1016/j.stem.2016.07.005. Epub 2016 Jul 28.

Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons.

Author information

1
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
2
Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
3
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; National Neuroscience Institute, 20 College Road, Singapore 169856, Singapore.
4
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
5
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
6
Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
7
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
9
School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Korea.
10
The Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
The Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
The Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.
13
The Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
14
National Neuroscience Institute, 20 College Road, Singapore 169856, Singapore.
15
Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: shawn.je@duke-nus.edu.sg.
16
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798, Singapore. Electronic address: nghh@gis.a-star.edu.sg.

Abstract

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.

PMID:
27476966
PMCID:
PMC5510242
DOI:
10.1016/j.stem.2016.07.005
[Indexed for MEDLINE]
Free PMC Article

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