Individual brain organoids reproducibly form cell diversity of the human cerebral cortex

被引:664
作者
Velasco, Silvia [1 ,2 ]
Kedaigle, Amanda J. [1 ,2 ,3 ]
Simmons, Sean K. [2 ,3 ]
Nash, Allison [1 ,2 ]
Rocha, Marina [1 ,2 ]
Quadrato, Giorgia [1 ,2 ,4 ]
Paulsen, Bruna [1 ,2 ]
Lan Nguyen [3 ]
Adiconis, Xian [2 ,3 ]
Regev, Aviv [3 ,5 ]
Levin, Joshua Z. [2 ,3 ]
Arlotta, Paola [1 ,2 ]
机构
[1] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[2] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA
[3] Broad Inst MIT & Harvard, Klarman Cell Observ, Cambridge, MA 02142 USA
[4] USC, Eli & Edythe Broad, CIRM Ctr Regenerat Med & Stem Cell Res, Los Angeles, CA USA
[5] MIT, Howard Hughes Med Inst, Koch Inst Integrat Canc Res, Dept Biol, Cambridge, MA USA
基金
美国国家卫生研究院;
关键词
SUBTYPE-SPECIFIC GENES; SELF-ORGANIZATION; MODELS; PROGENITOR; DYNAMICS; NEURONS;
D O I
10.1038/s41586-019-1289-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Experimental models of the human brain are needed for basic understanding of its development and disease(1). Human brain organoids hold unprecedented promise for this purpose; however, they are plagued by high organoid-to-organoid variability(2,3). This has raised doubts as to whether developmental processes of the human brain can occur outside the context of embryogenesis with a degree of reproducibility that is comparable to the endogenous tissue. Here we show that an organoid model of the dorsal forebrain can reliably generate a rich diversity of cell types appropriate for the human cerebral cortex. We performed single-cell RNA-sequencing analysis of 166,242 cells isolated from 21 individual organoids, finding that 95% of the organoids generate a virtually indistinguishable compendium of cell types, following similar developmental trajectories and with a degree of organoid-to-organoid variability comparable to that of individual endogenous brains. Furthermore, organoids derived from different stem cell lines show consistent reproducibility in the cell types produced. The data demonstrate that reproducible development of the complex cellular diversity of the central nervous system does not require the context of the embryo, and that establishment of terminal cell identity is a highly constrained process that can emerge from diverse stem cell origins and growth environments.
引用
收藏
页码:523 / +
页数:15
相关论文
共 40 条
[1]   Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo [J].
Arlotta, P ;
Molyneaux, BJ ;
Chen, J ;
Inoue, J ;
Kominami, R ;
Macklis, JD .
NEURON, 2005, 45 (02) :207-221
[2]  
Arlotta P, 2017, Protocol Exchange, DOI [10.1038/protex.2017.049, DOI 10.1038/PROTEX.2017.049]
[3]  
Arya S., 2018, RANN: Fast Nearest Neighbour Search (Wraps ANN Library) Using L2 Metric [R package version 2.6]
[4]   Fused cerebral organoids model interactions between brain regions [J].
Bagley, Joshua A. ;
Reumann, Daniel ;
Bian, Shan ;
Levi-Strauss, Julie ;
Knoblich, Juergen A. .
NATURE METHODS, 2017, 14 (07) :743-+
[5]   Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia [J].
Bershteyn, Marina ;
Nowakowski, Tomasz J. ;
Pollen, Alex A. ;
Di Lullo, Elizabeth ;
Nene, Aishwarya ;
Wynshaw-Boris, Anthony ;
Kriegstein, Arnold R. .
CELL STEM CELL, 2017, 20 (04) :435-+
[6]   Assembly of functionally integrated human forebrain spheroids [J].
Birey, Fikri ;
Andersen, Jimena ;
Makinson, Christopher D. ;
Islam, Saiful ;
Wei, Wu ;
Huber, Nina ;
Fan, H. Christina ;
Metzler, Kimberly R. Cordes ;
Panagiotakos, Georgia ;
Thom, Nicholas ;
O'Rourke, Nancy A. ;
Steinmetz, Lars M. ;
Bernstein, Jonathan A. ;
Hallmayer, Joachim ;
Huguenard, John R. ;
Pasca, Sergiu P. .
NATURE, 2017, 545 (7652) :54-+
[7]   Random forests [J].
Breiman, L .
MACHINE LEARNING, 2001, 45 (01) :5-32
[8]   Integrating single-cell transcriptomic data across different conditions, technologies, and species [J].
Butler, Andrew ;
Hoffman, Paul ;
Smibert, Peter ;
Papalexi, Efthymia ;
Satija, Rahul .
NATURE BIOTECHNOLOGY, 2018, 36 (05) :411-+
[9]   Human cerebral organoids recapitulate gene expression programs of fetal neocortex development [J].
Camp, J. Gray ;
Badsha, Farhath ;
Florio, Marta ;
Kanton, Sabina ;
Gerber, Tobias ;
Wilsch-Braeuninger, Michaela ;
Lewitus, Eric ;
Sykes, Alex ;
Hevers, Wulf ;
Lancaster, Madeline ;
Knoblich, Juergen A. ;
Lachmann, Robert ;
Paeaebo, Svante ;
Huttner, Wieland B. ;
Treutlein, Barbara .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (51) :15672-15677
[10]   The Personal Genome Project [J].
Church, G. M. .
MOLECULAR SYSTEMS BIOLOGY, 2005, 1 (1)