Abstract
Human cortical brain development is a tightly controlled and highly orchestrated process composed of neural progenitor cell (NPC) proliferation, migration, differentiation, and maturation. Recent advances in cerebral organoid technology have provided a means to model these complex cellular mechanisms to advance our understanding of normal human brain development and to provide molecular insight into the pathogenesis of brain disease. Cerebral organoids, which are generated from human pluripotent stem cells, are composed of three-dimensional neural tissue. This tissue can self-organize to form discrete regions of the human brain that includes cerebral cortex, choroid plexus, and others, if appropriate differentiation cues are present. Indeed, cerebral organoids provide an invaluable resource to study human-specific aspects of corticogenesis in vitro, such as investigating the function of outer radial glia (oRG), and other complex features of the human cerebral cortex. Here, we provide an overview of several methodologies to generate human cerebral organoids derived from human pluripotent stem cells including modifications from our laboratory. In addition, we highlight the advantages and current challenges associated with using cerebral organoids as an in vitro system to model human cortical brain development and disease.
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References
Fietz SA, Huttner WB (2011) Cortical progenitor expansion, self-renewal and neurogenesis-a polarized perspective. Curr Opin Neurobiol 21(1):23–35. doi:10.1016/j.conb.2010.10.002
Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, Espuny-Camacho I, Herpoel A, Passante L, Schiffmann SN, Gaillard A, Vanderhaeghen P (2008) An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455(7211):351–357. doi:10.1038/nature07287
Gotz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6(10):777–788. doi:10.1038/nrm1739
Manzini MC, Walsh CA (2011) What disorders of cortical development tell us about the cortex: one plus one does not always make two. Curr Opin Genet Dev 21(3):333–339. doi:10.1016/j.gde.2011.01.006
Chwalek K, Tang-Schomer MD, Omenetto FG, Kaplan DL (2015) In vitro bioengineered model of cortical brain tissue. Nat Protoc 10(9):1362–1373. doi:10.1038/nprot.2015.091
Schwartz MP, Hou Z, Propson NE, Zhang J, Engstrom CJ, Santos Costa V, Jiang P, Nguyen BK, Bolin JM, Daly W, Wang Y, Stewart R, Page CD, Murphy WL, Thomson JA (2015) Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A 112(40):12516–12521. doi:10.1073/pnas.1516645112
Otani T, Marchetto MC, Gage FH, Simons BD, Livesey FJ (2016) 2D and 3D stem cell models of primate cortical development identify species-specific differences in progenitor behavior contributing to brain size. Cell Stem Cell 18(4):467–480. doi:10.1016/j.stem.2016.03.003
Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, Yao B, Hamersky GR, Jacob F, Zhong C, Yoon KJ, Jeang W, Lin L, Li Y, Thakor J, Berg DA, Zhang C, Kang E, Chickering M, Nauen D, Ho CY, Wen Z, Christian KM, Shi PY, Maher BJ, Wu H, Jin P, Tang H, Song H, Ming GL (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165(5):1238–1254. doi:10.1016/j.cell.2016.04.032
Hattori N (2014) Cerebral organoids model human brain development and microcephaly. Mov Disord: Off J Mov Disord Soc 29(2):185. doi:10.1002/mds.25740
Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, Sasai Y (2013) Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A 110(50):20284–20289. doi:10.1073/pnas.1315710110
Lancaster MA, Knoblich JA (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9(10):2329–2340. doi:10.1038/nprot.2014.158
Lindborg BA, Brekke JH, Vegoe AL, Ulrich CB, Haider KT, Subramaniam S, Venhuizen SL, Eide CR, Orchard PJ, Chen W, Wang Q, Pelaez F, Scott CM, Kokkoli E, Keirstead SA, Dutton JR, Tolar J, O'Brien TD (2016) Rapid induction of cerebral organoids from human induced pluripotent stem cells using a chemically defined hydrogel and defined cell culture medium. Stem Cells Transl Med 5(7):970–979. doi:10.5966/sctm.2015-0305
Muzio L, Consalez GG (2013) Modeling human brain development with cerebral organoids. Stem Cell Res Ther 4(6):154. doi:10.1186/scrt384
Kirwan P, Turner-Bridger B, Peter M, Momoh A, Arambepola D, Robinson HP, Livesey FJ (2015) Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro. Development 142(18):3178–3187. doi:10.1242/dev.123851
Mariani J, Simonini MV, Palejev D, Tomasini L, Coppola G, Szekely AM, Horvath TL, Vaccarino FM (2012) Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A 109(31):12770–12775. doi:10.1073/pnas.1202944109
Pasca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, Kim CH, Park JY, O'Rourke NA, Nguyen KD, Smith SJ, Huguenard JR, Geschwind DH, Barres BA, Pasca SP (2015) Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12(7):671–678. doi:10.1038/nmeth.3415
Shi Y, Kirwan P, Livesey FJ (2012) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7(10):1836–1846. doi:10.1038/nprot.2012.116
Hester ME, Murtha MJ, Song S, Rao M, Miranda CJ, Meyer K, Tian J, Boulting G, Schaffer DV, Zhu MX, Pfaff SL, Gage FH, Kaspar BK (2011) Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol Ther: J Am Soc Gene Ther 19(10):1905–1912. doi:10.1038/mt.2011.135
Hester ME, Song S, Miranda CJ, Eagle A, Schwartz PH, Kaspar BK (2009) Two factor reprogramming of human neural stem cells into pluripotency. PLoS One 4(9):e7044. doi:10.1371/journal.pone.0007044
Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379. doi:10.1038/nature12517
Shamir ER, Ewald AJ (2014) Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol 15(10):647–664. doi:10.1038/nrm3873
Ranga A, Gjorevski N, Lutolf MP (2014) Drug discovery through stem cell-based organoid models. Adv Drug Deliv Rev 69-70:19–28. doi:10.1016/j.addr.2014.02.006
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This research was supported by Internal Research Funds by The Research Institute at Nationwide Children’s Hospital.
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Hester, M.E., Hood, A.B. (2017). Generation of Cerebral Organoids Derived from Human Pluripotent Stem Cells. In: Srivastava, A., Snyder, E., Teng, Y. (eds) Stem Cell Technologies in Neuroscience. Neuromethods, vol 126. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7024-7_8
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DOI: https://doi.org/10.1007/978-1-4939-7024-7_8
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