Browse > Article
http://dx.doi.org/10.14348/molcells.2019.0162

Past, Present, and Future of Brain Organoid Technology  

Koo, Bonsang (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
Choi, Baekgyu (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
Park, Hoewon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
Yoon, Ki-Jun (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
Abstract
Brain organoids are an exciting new technology with the potential to significantly change our understanding of the development and disorders of the human brain. With step-by-step differentiation protocols, three-dimensional neural tissues are self-organized from pluripotent stem cells, and recapitulate the major millstones of human brain development in vitro. Recent studies have shown that brain organoids can mimic the spatiotemporal dynamicity of neurogenesis, the formation of regional neural circuitry, and the integration of glial cells into a neural network. This suggests that brain organoids could serve as a representative model system to study the human brain. In this review, we will overview the development of brain organoid technology, its current progress and applications, and future prospects of this technology.
Keywords
brain disorder; brain organoid; neurodevelopment; pluripotent stem cell; three-dimensional culture;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Janssens, S., Schotsaert, M., Karnik, R., Balasubramaniam, V., Dejosez, M., Meissner, A., García-Sastre, A., and Zwaka, T.P. (2018). Zika virus alters DNA methylation of neural genes in an organoid model of the developing human brain. mSystems 3, e00219-e00217.
2 Jo, J., Xiao, Y., Sun, A.X., Cukuroglu, E., Tran, H.D., Göke, J., Tan, Z.Y., Saw, T.Y., Tan, C.P., Lokman, H., et al. (2016). Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19, 248-257.   DOI
3 Karzbrun, E., Kshirsagar, A., Cohen, S.R., Hanna, J.H., and Reiner, O. (2018). Human brain organoids on a chip reveal the physics of folding. Nat. Phys. 14, 515-522.   DOI
4 Karzbrun, E., Reiner, O., Karzbrun, E., and Reiner, O. (2019). Brain organoids-a bottom-up approach for studying human neurodevelopment. Bioengineering (Basel) 6, E9.   DOI
5 Kim, H., Park, H.J., Choi, H., Chang, Y., Park, H., Shin, J., Kim, J., Lengner, C.J., Lee, Y.K., and Kim, J. (2019a). Modeling G2019S-LRRK2 sporadic Parkinson's disease in 3D midbrain organoids. Stem Cell Reports 12, 518-531.   DOI
6 Kim, J., Koo, B.K., and Yoon, K.J. (2019b). Modeling host-virus interactions in viral infectious diseases using stem-cell-derived systems and CRISPR/Cas9 technology. Viruses 11, E124.   DOI
7 Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., and Jones, J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147.   DOI
8 Trujillo, C.A., Gao, R., Negraes, P.D., Gu, J., Buchanan, J., Preissl, S., Wang, A., Wu, W., Haddad, G.G., Chaim, I.A., et al. (2019). Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 1-12.   DOI
9 Tung, T.C. and Kü, S.H. (1944). Experimental studies on the development of the pronephric duct in anuran embryos. J. Anat. 78, 52-57.
10 Valiente, M. and Marin, O. (2010). Neuronal migration mechanisms in development and disease. Curr. Opin. Neurobiol. 20, 68-78.   DOI
11 Shi, Y., Kirwan, P., Smith, J., Robinson, H.P.C., and Livesey, F.J. (2012). Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477-486, S1.   DOI
12 Li, Y., Muffat, J., Omer, A., Bosch, I., Lancaster, M.A., Sur, M., Gehrke, L., Knoblich, J.A., and Jaenisch, R. (2017). Induction of expansion and folding in human cerebral organoids. Cell Stem Cell 20, 385-396.e3.   DOI
13 Kopper, O., de Witte, C.J., Lohmussaar, K., Valle-Inclan, J.E., Hami, N., Kester, L., Balgobind, A.V., Korving, J., Proost, N., Begthel, H., et al. (2019). An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat. Med. 25, 838-849.   DOI
14 van de Wetering, M., Francies, H.E., Francis, J.M., Bounova, G., Iorio, F., Pronk, A., van Houdt, W., van Gorp, J., Taylor-Weiner, A., Kester, L., et al. (2015). Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933-945.   DOI
15 Velasco, S., Kedaigle, A.J., Simmons, S.K., Nash, A., Rocha, M., Quadrato, G., Paulsen, B., Nguyen, L., Adiconis, X., Regev, A., et al. (2019). Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570, 523-527.   DOI
16 Kriegstein, A.R. and Noctor, S.C. (2004). Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 27, 392-399.   DOI
17 Lancaster, M.A. and Knoblich, J.A. (2014). Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125.   DOI
18 Lancaster, M.A., Renner, M., Martin, C.A., Wenzel, D., Bicknell, L.S., Hurles, M.E., Homfray, T., Penninger, J.M., Jackson, A.P., and Knoblich, J.A. (2013). Cerebral organoids model human brain development and microcephaly. Nature 501, 373-379.   DOI
19 Levitt, P. and Veenstra-VanderWeele, J. (2015). Neurodevelopment and the origins of brain disorders. Neuropsychopharmacology 40, 1-3.   DOI
20 Lin, Y.T., Seo, J., Gao, F., Feldman, H.M., Wen, H.L., Penney, J., Cam, H.P., Gjoneska, E., Raja, W.K., Cheng, J., et al. (2018). APOE4 causes widespread molecular and cellular alterations associated with Alzheimer's disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141-1154.e7.   DOI
21 Linkous, A., Balamatsias, D., Snuderl, M., Pisapia, D., Liston, C., and Correspondence, H.A.F. (2019). Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep. 26, 3203-3211.e5.   DOI
22 Lui, J.H., Hansen, D.V., and Kriegstein, A.R. (2011). Development and evolution of the human neocortex. Cell 146, 18-36.   DOI
23 Werner, S., Vu, H.T., and Rink, J.C. (2017). Self-organization in development, regeneration and organoids. Curr. Opin. Cell Biol. 44, 102-109.   DOI
24 Vijayavenkataraman, S., Yan, W.C., Lu, W.F., Wang, C.H., and Fuh, J.Y.H. (2018). 3D bioprinting of tissues and organs for regenerative medicine. Adv. Drug Deliv. Rev. 132, 296-332.   DOI
25 Wang, P., Mokhtari, R., Pedrosa, E., Kirschenbaum, M., Bayrak, C., Zheng, D., and Lachman, H.M. (2017). CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells. Mol. Autism 8, 11.   DOI
26 Watanabe, M., Buth, J.E., Vishlaghi, N., de la Torre-Ubieta, L., Taxidis, J., Khakh, B.S., Coppola, G., Pearson, C.A., Yamauchi, K., Gong, D., et al. (2017). Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Rep. 21, 517-532.   DOI
27 Wilson, H.V. (1907). On some phenomena of coalescence and regeneration in sponges. J. Exp. Zool. 5, 245-258.   DOI
28 Wimmer, R.A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J.A., et al. (2019). Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565, 505-510.   DOI
29 Madhavan, M., Nevin, Z.S., Shick, H.E., Garrison, E., Clarkson-Paredes, C., Karl, M., Clayton, B.L.L., Factor, D.C., Allan, K.C., and Barbar, L. (2018). Induction of myelinating oligodendrocytes in human cortical spheroids. Nat. Methods 15, 700-706.   DOI
30 Xia, Y., Sancho-Martinez, I., Nivet, E., Rodriguez Esteban, C., Campistol, J.M., and Izpisua Belmonte, J.C. (2014). The generation of kidney organoids by differentiation of human pluripotent cells to ureteric bud progenitor-like cells. Nat. Protoc. 9, 2693-2704.   DOI
31 Mansour, A.A., Gonçalves, J.T., Bloyd, C.W., Li, H., Fernandes, S., Quang, D., Johnston, S., Parylak, S.L., Jin, X., and Gage, F.H. (2018). An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432-441.   DOI
32 Mariani, J., Coppola, G., Zhang, P., Abyzov, A., Provini, L., Tomasini, L., Amenduni, M., Szekely, A., Palejev, D., Wilson, M., et al. (2015). FOXG1-dependent dysregulation of GABA/Glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375-390.   DOI
33 Martin, G.R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. U. S. A. 78, 7634-7638.   DOI
34 Marton, R.M., Miura, Y., Sloan, S.A., Li, Q., Revah, O., Levy, R.J., Huguenard, J.R., and Pasca, S.P. (2019). Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat. Neurosci. 22, 484-491.   DOI
35 Mitchell, K.J. (2011). The genetics of neurodevelopmental disease. Curr. Opin. Neurobiol. 21, 197-203.   DOI
36 Mlakar, J., Korva, M., Tul, N., Popović, M., Poljsak-Prijatelj, M., Mraz, J., Kolenc, M., Resman Rus, K., Vesnaver Vipotnik, T., Fabjan Vodusek, V., et al. (2016). Zika virus associated with microcephaly. N. Engl. J. Med. 374, 951-958.   DOI
37 Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K., and Sasai, Y. (2015). Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 10, 537-550.   DOI
38 Yan, H.H.N., Siu, H.C., Law, S., Ho, S.L., Yue, S.S.K., Tsui, W.Y., Chan, D., Chan, A.S., Ma, S., Lam, K.O., et al. (2018). A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell 23, 882-897.e11.   DOI
39 Xu, M., Lee, E.M., Wen, Z., Cheng, Y., Huang, W.K., Qian, X., Tcw, J., Kouznetsova, J., Ogden, S.C., Hammack, C., et al. (2016). Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 22, 1101-1107.   DOI
40 Yamanaka, S. (2012). Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10, 678-684.   DOI
41 Yin, X., Mead, B.E., Safaee, H., Langer, R., Karp, J.M., and Levy, O. (2016). Engineering stem cell organoids. Cell Stem Cell 18, 25-38.   DOI
42 Yoon, K.J., Nguyen, H.N., Ursini, G., Zhang, F., Kim, N.S., Wen, Z., Makri, G., Nauen, D., Shin, J.H., Park, Y., et al. (2014). Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15, 79-91.   DOI
43 Yoon, K.J., Ringeling, F.R., Vissers, C., Jacob, F., Pokrass, M., Jimenez-Cyrus, D., Su, Y., Kim, N.S., Zhu, Y., Zheng, L., et al. (2017a). Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell 171, 877-889.e17.   DOI
44 Yoon, K.J., Song, G., Qian, X., Pan, J., Xu, D., Rho, H.S., Kim, N.S., Habela, C., Zheng, L., Jacob, F., et al. (2017b). Zika-virus-encoded NS2A disrupts mammalian cortical neurogenesis by degrading adherens junction proteins. Cell Stem Cell 21, 349-358.e6.   DOI
45 Charras, G. and Yap, A.S. (2018). Tensile forces and mechanotransduction at cell-cell junctions. Curr. Biol. 28, R445-R457.   DOI
46 Murphy, S.V. and Atala, A. (2014). 3D bioprinting of tissues and organs. Nat. Biotechnol. 32, 773-785.   DOI
47 Bian, S., Repic, M., Guo, Z., Kavirayani, A., Burkard, T., Bagley, J.A., Krauditsch, C., and Knoblich, J.A. (2018). Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods 15, 631-639.   DOI
48 Birey, F., Andersen, J., Makinson, C.D., Islam, S., Wei, W., Huber, N., Fan, H.C., Metzler, K.R.C., Panagiotakos, G., Thom, N., et al. (2017). Assembly of functionally integrated human forebrain spheroids. Nature 545, 54-59.   DOI
49 Buchanan, M. (2018). Organoids of intelligence. Nat. Phys. 14, 634.   DOI
50 Camp, J.G., Badsha, F., Florio, M., Kanton, S., Gerber, T., Wilsch-Brauninger, M., Lewitus, E., Sykes, A., Hevers, W., Lancaster, M., et al. (2015). Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl. Acad. Sci. U. S. A. 112, 15672-15677.   DOI
51 Choi, Y.H. and Kim, J.K. (2019). Dissecting cellular heterogeneity using single-cell RNA sequencing. Mol. Cells 42, 189-199.   DOI
52 Cugola, F.R., Fernandes, I.R., Russo, F.B., Freitas, B.C., Dias, J.L.M., Guimarães, K.P., Benazzato, C., Almeida, N., Pignatari, G.C., Romero, S., et al. (2016). The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267-271.   DOI
53 Park, S.E., Georgescu, A., and Huh, D. (2019). Organoids-on-a-chip. Science 364, 960-965.   DOI
54 Ogawa, J., Pao, G.M., Shokhirev, M.N., and Verma, I.M. (2018). Glioblastoma model using human cerebral organoids. Cell Rep. 23, 1220-1229.   DOI
55 Oh, Y. and Jang, J. (2019). Directed differentiation of pluripotent stem cells by transcription factors. Mol. Cells 42, 200-209.   DOI
56 Ormel, P.R., Vieira de Sa, R., van Bodegraven, E.J., Karst, H., Harschnitz, O., Sneeboer, M.A.M., Johansen, L.E., van Dijk, R.E., Scheefhals, N., Berdenis van Berlekom, A., et al. (2018). Microglia innately develop within cerebral organoids. Nat. Commun. 9, 4167.   DOI
57 Pasca, A.M., Park, J.Y., Shin, H.W., Qi, Q., Revah, O., Krasnoff, R., O'Hara, R., Willsey, A.J., Palmer, T.D., and Pasca, S.P. (2019). Human 3D cellular model of hypoxic brain injury of prematurity. Nat. Med. 25, 784-791.   DOI
58 Pasca, A.M., Sloan, S.A., Clarke, L.E., Tian, Y., Makinson, C.D., Huber, N., Kim, C.H., Park, J.Y., O'Rourke, N.A., Nguyen, K.D., et al. (2015). Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671-678.   DOI
59 Plummer, S., Wallace, S., Ball, G., Lloyd, R., Schiapparelli, P., Quinones-Hinojosa, A., Hartung, T., and Pamies, D. (2019). A human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine. Sci. Rep. 9, 1407.   DOI
60 Qian, X., Jacob, F., Song, M.M., Nguyen, H.N., Song, H., and Ming, G.l. (2018). Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat. Protoc. 13, 565-580.   DOI
61 Zhang, S.C., Wernig, M., Duncan, I.D., Brustle, O., and Thomson, J.A. (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129-1133.   DOI
62 Yoon, S.J., Elahi, L.S., Pasca, A.M., Marton, R.M., Gordon, A., Revah, O., Miura, Y., Walczak, E.M., Holdgate, G.M., Fan, H.C., et al. (2019). Reliability of human cortical organoid generation. Nat. Methods 16, 75-78.   DOI
63 Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.   DOI
64 Yuan, L., Huang, X.Y., Liu, Z.Y., Zhang, F., Zhu, X.L., Yu, J.Y., Ji, X., Xu, Y.P., Li, G., Li, C., et al. (2017). A single mutation in the prM protein of Zika virus contributes to fetal microcephaly. Science 358, 933-936.   DOI
65 Zhong, X., Gutierrez, C., Xue, T., Hampton, C., Vergara, M.N., Cao, L.H., Peters, A., Park, T.S., Zambidis, E.T., Meyer, J.S., et al. (2014). Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat. Commun. 5, 4047.   DOI
66 Zhou, T., Tan, L., Cederquist, G.Y., Fan, Y., Hartley, B.J., Mukherjee, S., Tomishima, M., Brennand, K.J., Zhang, Q., Schwartz, R.E., et al. (2017). Highcontent screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult brain. Cell Stem Cell 21, 274-283.e5.   DOI
67 Qian, X., Nguyen, H.N., Song, M.M., Hadiono, C., Ogden, S.C., Hammack, C., Yao, B., Hamersky, G.R., Jacob, F., Zhong, C., et al. (2016). Brain-regionspecific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238-1254.   DOI
68 Czerniecki, S.M., Cruz, N.M., Harder, J.L., Menon, R., Annis, J., Otto, E.A., Gulieva, R.E., Islas, L.V., Kim, Y.K., Tran, L.M., et al. (2018). Highthroughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping. Cell Stem Cell 22, 929-940.e4.   DOI
69 Dang, J., Tiwari, S.K., Lichinchi, G., Qin, Y., Patil, V.S., Eroshkin, A.M., and Rana, T.M. (2016). Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 19, 258-265.   DOI
70 Dawson, T.M., Ko, H.S., and Dawson, V.L. (2010). Genetic animal models of Parkinson's disease. Neuron 66, 646-661.   DOI
71 Raja, W.K., Mungenast, A.E., Lin, Y.T., Ko, T., Abdurrob, F., Seo, J., and Tsai, L.H. (2016). Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer's disease phenotypes. PLoS One 11, 1-18.
72 Zwilling, E. (1960). Some aspects of differentiation: disaggregation and reaggregation of early chick embryos. Natl. Cancer Inst. Monogr. 2, 19-39.
73 Eiraku, M., Takata, N., Ishibashi, H., Kawada, M., Sakakura, E., Okuda, S., Sekiguchi, K., Adachi, T., and Sasai, Y. (2011). Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51-56.   DOI
74 Eiraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Matsumura, M., Wataya, T., Nishiyama, A., Muguruma, K., and Sasai, Y. (2008). Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519-532.   DOI
75 Gabriel, E., Ramani, A., Karow, U., Gottardo, M., Natarajan, K., Gooi, L.M., Goranci-Buzhala, G., Krut, O., Peters, F., Nikolic, M., et al. (2017). Recent Zika virus isolates induce premature differentiation of neural progenitors in human brain organoids. Cell Stem Cell 20, 397-406.e5.   DOI
76 Garcez, P.P., Loiola, E.C., Madeiro da Costa, R., Higa, L.M., Trindade, P., Delvecchio, R., Nascimento, J.M., Brindeiro, R., Tanuri, A., and Rehen, S.K. (2016). Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816-818.   DOI
77 Qian, X., Song, H., and Ming, G.L. (2019). Brain organoids: advances, applications and challenges. Development 146, dev166074.
78 Quadrato, G., Nguyen, T., Macosko, E.Z., Sherwood, J.L., Min Yang, S., Berger, D.R., Maria, N., Scholvin, J., Goldman, M., Kinney, J.P., et al. (2017). Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48-53.   DOI
79 Raslan, A.A. and Kee, Y. (2013). Tackling neurodegenerative diseases: animal models of Alzheimer's disease and Parkinson's disease. Genes Genom. 35, 425-440.   DOI
80 Sachs, N., de Ligt, J., Kopper, O., Gogola, E., Bounova, G., Weeber, F., Balgobind, A.V., Wind, K., Gracanin, A., Begthel, H., et al. (2018). A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373-386.e10.   DOI
81 Schafer, S.T., Paquola, A.C.M., Stern, S., Gosselin, D., Ku, M., Pena, M., Kuret, T.J.M., Liyanage, M., Mansour, A.A., Jaeger, B.N., et al. (2019). Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat. Neurosci. 22, 243-255.   DOI
82 Calvet, G., Aguiar, R.S., Melo, A.S.O., Sampaio, S.A., de Filippis, I., Fabri, A., Araujo, E.S.M., de Sequeira, P.C., de Mendonça, M.C.L., de Oliveira, L., et al. (2016). Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect. Dis. 16, 653-660.   DOI
83 Gaspard, N., Bouschet, T., Hourez, R., Dimidschstein, J., Naeije, G., Van den Ameele, J., Espuny-Camacho, I., Herpoel, A., Passante, L., and Schiffmann, S.N. (2008). An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455, 351-357.   DOI
84 Grebenyuk, S. and Ranga, A. (2019). Engineering organoid vascularization. Front. Bioeng. Biotechnol. 7, 39.   DOI
85 Heymann, D.L., Hodgson, A., Sall, A.A., Freedman, D.O., Staples, J.E., Althabe, F., Baruah, K., Mahmud, G., Kandun, N., Vasconcelos, P.F., et al. (2016). Zika virus and microcephaly: why is this situation a PHEIC? Lancet 387, 719-721.   DOI
86 Hockemeyer, D. and Jaenisch, R. (2016). Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18, 573-586.   DOI
87 Sakaguchi, H., Kadoshima, T., Soen, M., Narii, N., Ishida, Y., Ohgushi, M., Takahashi, J., Eiraku, M., and Sasai, Y. (2015). Generation of functional hippocampal neurons from self-organizing human embryonic stem cellderived dorsomedial telencephalic tissue. Nat. Commun. 6, 8896.   DOI
88 Sato, T., Vries, R.G., Snippert, H.J., van de Wetering, M., Barker, N., Stange, D.E., van Es, J.H., Abo, A., Kujala, P., Peters, P.J., et al. (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262-265.   DOI
89 Hubert, C.G., Rivera, M., Spangler, L.C., Wu, Q., Mack, S.C., Prager, B.C., Couce, M., McLendon, R.E., Sloan, A.E., and Rich, J.N. (2016). A threedimensional organoid culture system derived from human glioblastomas recapitulates the hypoxic gradients and cancer stem cell heterogeneity of tumors found in vivo. Cancer Res. 76, 2465-2477.   DOI
90 Homem, C.C.F., Repic, M., and Knoblich, J.A. (2015). Proliferation control in neural stem and progenitor cells. Nat. Rev. Neurosci. 16, 647-659.   DOI
91 Tao, Y. and Zhang, S.C. (2016). Neural subtype specification from human pluripotent stem cells. Cell Stem Cell 19, 573-586.   DOI
92 Sloan, S.A., Darmanis, S., Huber, N., Khan, T.A., Birey, F., Caneda, C., Reimer, R., Quake, S.R., Barres, B.A., and Paşca, S.P. (2017). Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95, 779-790.e6.   DOI
93 Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872.   DOI
94 Takahashi, K. and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.   DOI