A major breakthrough in the stem cell field over the last decade has been the development of technology to reprogram human somatic cells into induced pluripotent stem cells or iPSCs. In addition to the ability to derive specific cell types from human iPSCs in dish as 2D cultures, rapid progress in the field has made it possible to generate 3D cultures, or organoids, from iPSCs resembling whole developing organs, including intestinal, kidney, retinal, and cerebral cortex. Human organoids provide a unique opportunity to model organ development in a culture system that is similar to human organogenesis in vivo. Furthermore, organoid cultures provide the opportunity to model diseases that affect multiple cell types and to investigate non-cell- autonomous effects. The work in my laboratory focuses on neural development using both mouse models and iPSC models; and our long term goal is to understand mechanisms underlying normal brain development, neurodevelopmental diseases and to aid in the development of rational therapeutic strategies. Despite the tremendous promise of cerebral organoids to model brain genesis and brain diseases, there are several major limitations of the currently available technology, including high cost, low reproducibility and high variability, that limit our ability for quantitative analyses and broad application of the technology. We have recently developed a new approach by miniaturizing the critical components used to generate cerebral organoids, which allows for a dramatic reduction in materials, cell culture media, space and costs. In this exploratory project, we propose to further standardize forebrain specific organoid production and optimize cell culture conditions for directed and sustained growth. As a proof-of-principle, we will use this system to test the hypothesis that 15q11.2 microdeletion, a prominent genetic risk factor for epilepsy, leads to aberrant cortical neurogenesis for seizure susceptibility. We believe that our approach will transform organogenesis modeling and facilitate the identification of disease-relevant biological processes that are difficult to recapitulate in 2D monolayer cultures.

Public Health Relevance

Early human brain development and neurogenic events can be recapitulated by a new, 3D-cerebral organoid- culture technology from pluripotent stem cells. Combining this technology with improved consistency and lower costs and human induced pluripotent stem cells harboring the 15q11.2 microdeletion associated with epilepsy risk, we aim to identify aberrant early neurogenic/developmental events that might contribute to the development of epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS095348-01
Application #
9033555
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Lavaute, Timothy M
Project Start
2015-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Yoon, Ki-Jun; Ming, Guo-Li; Song, Hongjun (2018) Coupling Neurogenesis to Circuit Formation. Cell 173:288-290
Yoon, Ki-Jun; Ming, Guo-Li; Song, Hongjun (2018) Epitranscriptomes in the Adult Mammalian Brain: Dynamic Changes Regulate Behavior. Neuron 99:243-245
Qian, Xuyu; Jacob, Fadi; Song, Mingxi Max et al. (2018) Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc 13:565-580
Ye, Fei; Kang, Eunchai; Yu, Chuan et al. (2017) DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron 96:1204
Yoon, Ki-Jun; Ringeling, Francisca Rojas; Vissers, Caroline et al. (2017) Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell 171:877-889.e17
Ye, Fei; Kang, Eunchai; Yu, Chuan et al. (2017) DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron 96:1041-1054.e5
Yoon, Ki-Jun; Song, Guang; Qian, Xuyu et al. (2017) Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins. Cell Stem Cell 21:349-358.e6
Oh, Yohan; Zhang, Feiran; Wang, Yaqing et al. (2017) Zika virus directly infects peripheral neurons and induces cell death. Nat Neurosci 20:1209-1212
Habela, Christa W; Song, Hongjun; Ming, Guo-Li (2016) Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons. Mol Cell Neurosci 73:52-62
Zeng, Yaxue; Yao, Bing; Shin, Jaehoon et al. (2016) Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression. Mol Cell 61:153-60

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