Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem Cells

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2017 Apr 19

PMID 28416282

Citations 179

Authors

Anna S Monzel

Lisa M Smits

Kathrin Hemmer

Siham Hachi

Edinson Lucumi Moreno

Thea van Wuellen

Javier Jarazo

Jonas Walter

Inga Bruggemann

Ibrahim Boussaad

Emanuel Berger

Ronan M T Fleming

Silvia Bolognin

Jens C Schwamborn

Affiliations

Soon will be listed here.

Abstract

Research on human brain development and neurological diseases is limited by the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Here, we describe a robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. These human midbrain organoids contain spatially organized groups of dopaminergic neurons, which make them an attractive model for the study of Parkinson's disease. Midbrain organoids are characterized in detail for neuronal, astroglial, and oligodendrocyte differentiation. Furthermore, we show the presence of synaptic connections and electrophysiological activity. The complexity of this model is further highlighted by the myelination of neurites. The present midbrain organoid system has the potential to be used for advanced in vitro disease modeling and therapy development.

Citing Articles

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References

Baharvand H, Hashemi S, Kazemi Ashtiani S, Farrokhi A . Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol. 2006; 50(7):645-52. DOI: 10.1387/ijdb.052072hb. View

Bunk E, Ertaylan G, Ortega F, Pavlou M, Cano L, Stergiopoulos A . Prox1 Is Required for Oligodendrocyte Cell Identity in Adult Neural Stem Cells of the Subventricular Zone. Stem Cells. 2016; 34(8):2115-29. DOI: 10.1002/stem.2374. View

Duan D, Fu Y, Paxinos G, Watson C . Spatiotemporal expression patterns of Pax6 in the brain of embryonic, newborn, and adult mice. Brain Struct Funct. 2012; 218(2):353-72. DOI: 10.1007/s00429-012-0397-2. View

Reinhardt P, Glatza M, Hemmer K, Tsytsyura Y, Thiel C, Hoing S . Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling. PLoS One. 2013; 8(3):e59252. PMC: 3606479. DOI: 10.1371/journal.pone.0059252. View

Garcia-Reitboeck P, Anichtchik O, Dalley J, Ninkina N, Tofaris G, Buchman V . Endogenous alpha-synuclein influences the number of dopaminergic neurons in mouse substantia nigra. Exp Neurol. 2013; 248:541-5. PMC: 4104299. DOI: 10.1016/j.expneurol.2013.07.015. View

Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K . Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012; 10(6):771-785. DOI: 10.1016/j.stem.2012.05.009. View

Muguruma K, Nishiyama A, Kawakami H, Hashimoto K, Sasai Y . Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 2015; 10(4):537-50. DOI: 10.1016/j.celrep.2014.12.051. View

Qian X, Nguyen H, Song M, Hadiono C, Ogden S, Hammack C . Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell. 2016; 165(5):1238-1254. PMC: 4900885. DOI: 10.1016/j.cell.2016.04.032. View

Le Grand J, Gonzalez-Cano L, Pavlou M, Schwamborn J . Neural stem cells in Parkinson's disease: a role for neurogenesis defects in onset and progression. Cell Mol Life Sci. 2014; 72(4):773-97. PMC: 11113294. DOI: 10.1007/s00018-014-1774-1. View

10.

Faivre-Sarrailh C, Devaux J . Neuro-glial interactions at the nodes of Ranvier: implication in health and diseases. Front Cell Neurosci. 2013; 7:196. PMC: 3810605. DOI: 10.3389/fncel.2013.00196. View

11.

Hartfield E, Yamasaki-Mann M, Ribeiro Fernandes H, Vowles J, James W, Cowley S . Physiological characterisation of human iPS-derived dopaminergic neurons. PLoS One. 2014; 9(2):e87388. PMC: 3931621. DOI: 10.1371/journal.pone.0087388. View

12.

Tian X, Heng B, Ge Z, Lu K, Rufaihah A, Fan V . Comparison of osteogenesis of human embryonic stem cells within 2D and 3D culture systems. Scand J Clin Lab Invest. 2008; 68(1):58-67. DOI: 10.1080/00365510701466416. View

13.

McBeath R, Pirone D, Nelson C, Bhadriraju K, Chen C . Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. 2004; 6(4):483-95. DOI: 10.1016/s1534-5807(04)00075-9. View

14.

Jo J, Xiao Y, Sun A, Cukuroglu E, Tran H, Goke J . Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell. 2016; 19(2):248-257. PMC: 5510242. DOI: 10.1016/j.stem.2016.07.005. View

15.

Jablonska B, Aguirre A, Raymond M, Szabo G, Kitabatake Y, Sailor K . Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat Neurosci. 2010; 13(5):541-550. PMC: 4059417. DOI: 10.1038/nn.2536. View

16.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

17.

Chung W, Welsh C, Barres B, Stevens B . Do glia drive synaptic and cognitive impairment in disease?. Nat Neurosci. 2015; 18(11):1539-1545. PMC: 4739631. DOI: 10.1038/nn.4142. View

18.

Tanaka H, Murphy C, Murphy C, Kimura M, Kawai S, Polak J . Chondrogenic differentiation of murine embryonic stem cells: effects of culture conditions and dexamethasone. J Cell Biochem. 2004; 93(3):454-62. DOI: 10.1002/jcb.20171. View

19.

Lee G, Kenny P, Lee E, Bissell M . Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods. 2007; 4(4):359-65. PMC: 2933182. DOI: 10.1038/nmeth1015. View

20.

Yu J, Vodyanik M, Smuga-Otto K, Antosiewicz-Bourget J, Frane J, Tian S . Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318(5858):1917-20. DOI: 10.1126/science.1151526. View