Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure

被引：1563

作者：

Qian, Xuyu ^{[1
,2
]}

Ha Nam Nguyen ^{[1
,3
]}

Song, Mingxi M. ^{[1
,9
]}

Hadiono, Christopher ^{[1
,10
]}

Ogden, Sarah C. ^{[11
]}

Hammack, Christy ^{[11
]}

Yao, Bing ^{[12
]}

Hamersky, Gregory R. ^{[5
]}

Jacob, Fadi ^{[1
]}

Zhong, Chun ^{[1
,4
]}

Yoon, Ki-Jun ^{[1
,4
]}

Jeang, William ^{[1
,14
]}

Lin, Li ^{[12
]}

Li, Yujing ^{[12
]}

Thakor, Jai ^{[1
]}

Berg, Daniel A. ^{[1
]}

Zhang, Ce ^{[1
,4
]}

Kang, Eunchai ^{[1
,4
]}

Chickering, Michael ^{[1
]}

Nauen, David ^{[1
,6
]}

Ho, Cheng-Ying ^{[15
,16
]}

Wen, Zhexing ^{[1
,4
]}

Christian, Kimberly M. ^{[1
,4
]}

Shi, Pei-Yong ^{[17
]}

Maher, Brady J. ^{[5
,7
]}

Wu, Hao ^{[13
]}

Jin, Peng ^{[12
]}

Tang, Hengli ^{[11
]}

Song, Hongjun ^{[1
,3
,4
,8
]}

Ming, Guo-li ^{[1
,3
,4
,7
,8
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Biomed Engn Grad Program, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Grad Program Cellular & Mol Med, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Solomon Snyder Dept Neurosci, Baltimore, MD 21205 USA

[9] Riverhill High Sch, Clarksville, MD 21029 USA

[10] Byram Hills High Sch, Armonk, NY 10504 USA

[11] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA

[12] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[13] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA

[14] Clear Lake High Sch, Harris, TX 77058 USA

[15] Childrens Natl Med Ctr, Div Pathol, Washington, DC 20010 USA

[16] George Washington Univ, Pathol & Pediat, Washington, DC 20010 USA

[17] Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

来源：

CELL | 2016年 / 165卷 / 05期

关键词：

SELF-ORGANIZATION; DIFFERENTIATION; TISSUE; CELLS; DYSREGULATION; NEURONS; RISK; MICE;

D O I：

10.1016/j.cell.2016.04.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigatehuman brain development. High cost, variability, and tissue heterogeneity limit their broad applications. Here, we developed a miniaturized spinning bioreactor (Spin Omega) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and Spin Omega provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.

引用

页码：1238 / 1254

页数：17

共 36 条

[1]

[Anonymous], CELL STEM CELL

[2]

[Anonymous], LANCET

[3]

[Anonymous], LANCET INFECT DIS

[4]

[Anonymous], N ENGL J MED

[5]

Bayer A., 2016, CELL HOST MICROBE

[6] Nature and nurture in brain development [J].

Ben-Ari, Y ;

Spitzer, NC .

TRENDS IN NEUROSCIENCES, 2004, 27 (07) :361-361

[7] Molecular Pathways Controlling Development of Thalamus and Hypothalamus: From Neural Specification to Circuit Formation [J].

Blackshaw, Seth ;

Scholpp, Steffen ;

Placzek, Marysia ;

Ingraham, Holly ;

Simerly, Richard ;

Shimogori, Tomomi .

JOURNAL OF NEUROSCIENCE, 2010, 30 (45) :14925-14930

[8] The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons [J].

Chung, S ;

Hedlund, E ;

Hwang, M ;

Kim, DW ;

Shin, BS ;

Hwang, DY ;

Kang, UJ ;

Isacson, O ;

Kim, KS .

MOLECULAR AND CELLULAR NEUROSCIENCE, 2005, 28 (02) :241-252

[9] Subregional Specification of Embryonic Stem Cell-Derived Ventral Telencephalic Tissues by Timed and Combinatory Treatment with Extrinsic Signals [J].

Danjo, Teruko ;

Eiraku, Mototsugu ;

Muguruma, Keiko ;

Watanabe, Kiichi ;

Kawada, Masako ;

Yanagawa, Yuchio ;

Rubenstein, John L. R. ;

Sasai, Yoshiki .

JOURNAL OF NEUROSCIENCE, 2011, 31 (05) :1919-1933

[10]

Faria N. R., 2016, SCIENCE

← 1 2 3 4 →