Brain Organoids


Recent developments in stem cell technologies are extending the boundaries forward to produce not only specific cell types but also even complex 3D structures, such as organoids, ‘mini organs in dish’. One such type is brain organoids derived from human pluripotent stem cells. Brain organoids consist of various cell types of ectodermal lineage and self‐assemble into organised structures resembling early human brain. Brain organoids exhibit ventricular zones (VZs) consisting of highly proliferative neural stem cells. During neurogenesis, neural stem cells differentiate and migrate from the VZ to the marginal zone of the organoid to form a primitive cortical plate by differentiating to neurons.

Brain organoids provide novel insights into human brain development and give new opportunities to study neurodevelopmental disorders such as microcephaly in vitro. In future, brain organoids can serve as a useful tool to model neurodegenerative disorders in humans and for therapeutic screening and drug testing in high‐throughput assays.

Key Concepts

  • Human 3D cell culture models are an alternative to animal models to study developmental diseases in humans.
  • Pluripotent stem cells can differentiate into complex 3D organoids.
  • Differentiating cells self‐assemble to form tissue‐like structures.
  • Brain organoids recapitulate important aspects of human brain development.
  • Brain organoids recapitulate early events in human brain development.
  • Brain organoids serve as a tool to model neurodevelopmental and neurodegenerative diseases.
  • Brain organoids can be used in high‐throughput assays for drug screening and toxicity testing.

Keywords: brain organoids; pluripotent stem cells; human iPSC; neurodevelopment; neural stem cells; primitive cortical plate; neurogenesis; microcephaly; in vitro differentiation

Figure 1. Human brain organoids derived from iPS cells of a healthy donor (wild type) and of a microcephaly (MCPH) patient. (a) Macroscopic view of 14‐day‐old human brain organoids generated from wild‐type human iPS cells. (i) Organoids are relatively homogenous in size and shape. (ii) An organoid in higher magnification harbouring fluid‐filled cavities (arrow) and resembling human embryonic brain. (b) Upper panel shows 14‐day‐old human brain organoids from healthy donor iPS cells. Bottom panel shows age‐matched human brain organoids derived from a MCPH patient. (c) Immunofluorescent images of 14‐day‐old human brain organoids cryosectioned in 20‐µm‐thin sections. (i) Organoid from a healthy donor with Pax6‐positive neural stem cells residing in the VZ (magenta) nearby the lumen (L). TUJ1‐positive neurons (green) are forming the primitive cortical plate in the periphery of the organoid. (ii) Immunofluorescent staining of a cryosectioned 14‐day‐old organoid generated from a MCPH patient. Note the larger lumen (L), lesser number of Pax6‐positive cells in the thus thinner VZ and the thinner cortical area containing TUJ1‐positive neurons (green) compared to organoid from healthy donor. Reproduced with permission from Gabriel et al. 2016 © EMBO.
Figure 2. Symmetrically and asymmetrically dividing aRG cells in the VZ. (a) Overview of a ventricular zone (VZ) containing dividing aRG cells at the apical side of the VZ labelled by phospho‐vimentin (pVim; magenta) towards the lumen (L), which is surrounded by Arl13b‐positive cilia from aRG cells (green). Right‐side image illustrates a symmetrically dividing aRG (bottom) with division plane horizontal to the luminar surface and an asymmetrically dividing aRG (upper) with a vertically oriented division plane. (b) High magnification of the symmetrically dividing aRG. Note that the division plane is clearly visible as this cell is in anaphase of mitosis. Right schematic shows the horizontal division plane parallel to the luminar surface. (c) High magnification of the asymmetrically diving aRG in anaphase of mitosis. Right schematic shows vertical division plane perpendicular to the luminar surface. Reproduced from Gabriel et al. 2017 © Elsevier.
Figure 3. Modelling Zika virus‐induced microcephaly (MCPH) during early human brain development. (a) Model of how Zika virus might cause MCPH during early human brain development. (i) Blue area is the ventricular zone (VZ) with mainly symmetrically dividing radial glial (RG) cells. White area is the intermediate zone through which differentiating cells migrate to form the newly born neurons (magenta) in the primitive cortical plate (yellow area). Red colour indicates the primary cilium of the apical RG cells protruding into the lumen of the VZ inside the organoid. (ii) Zika virus (green) infects and replicates preferably in apical RG cells. Infected RG cells then prematurely differentiate from symmetric to asymmetric cell division, illustrated by newly born neurons (magenta) within the VZ. This leads to a reduced thickness of VZ and cortical plate compared to noninfected left panel. Zika virus‐infected differentiated cells then show enhanced apoptosis when they reach primitive cortical plate. (b) Immunofluorescent staining of an 11‐day‐old human brain organoid derived from human‐induced pluripotent stem cells infected for 2 days with a recent Zika virus isolate. In (i), all channels are shown as merged. Proliferating aRG cells in the VZ are preferably targeted by Zika virus (ii, green) and start differentiation and migration towards the cortical plate upon (iii, magenta) where they undergo apoptosis eventually (iv, yellow). Reproduced from Gabriel et al. 2017 © Elsevier.


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Gabriel, Elke, and Gopalakrishnan, Jay(Nov 2017) Brain Organoids. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027186]