From Neural Induction in Frogs to Human Brains on Chips

Abstract

The entire nervous system of the vertebrate embryo is derived from an epithelium sheet called the neural plate, which is induced by the organizer/node at the onset of gastrulation. Dissection of the molecular network underlying the emergence of the neural plate, originally performed in Xenopus embryos, led to the discovery of the TGFβ double inhibition mechanism for neural induction, coined ‘the default model’. Years later, these developmental principles have been translated in vitro to instruct human pluripotent stem cells towards neural fate and to build brain organoids.

Key Concepts

  • The Spemann organizer is defined by the capability of a group of cells in a transplantation experiment to induce, in a non‐cell‐autonomous fashion, a secondary neural axis and to autonomously differentiate into axial and paraxial mesoderm derivatives.
  • Neural fate acquisition both in vivo in the embryo and in vitro from pluripotent stem cells is the result of blocking the ongoing TGFβ pathway, both Activin‐Nodal and BMP branches.
  • Embryonic stem cells are defined based on two basic properties: their ability to maintain their undifferentiated state (stemness) indefinitely and to be able to differentiate into cell types derived from the three embryonic germ layers (pluripotency).
  • Brain organoids are 3D in vitro structures that resemble several features of the developing human brain.
  • Human pluripotent stem cells cultured in confined geometry (micropattern) self‐organized into defined embryonic structures with standardised cytoarchitecture and distinct cell fates.

Keywords: neural default; brain organoids; cerebroids; neuruloids; micropattern

Figure 1. Collection of in vitro neural structures. (a) Schematic representation of self‐patterning organoids. Several lumens are represented by yellow and black circles (apical domain). Colours indicate several different cell types in the organoids. Based on Lancaster, M., Renner, M., Martin, C. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (). (b) Self‐patterning organoids that use a polymeric scaffold to standardise differentiation process. Colours indicate several different cell types in the organoids. Based on Lancaster, M., Corsini, N., Wolfinger, S. et al. Guided self‐organization and cortical plate formation in human brain organoids. Nat Biotechnol 35, 659–666 (). (c) Individually patterned dorsal (Blue) and ventral (Red) forebrain spheroids that are fused together forming a Dorsal‐Ventral assembled forebrain structure. Based on Birey, F., Andersen, J., Makinson, C. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54–59 (). (d) Specification of dorsal and ventral forebrain positional identity using a localised SHH source, produced by a clump of cells (Grey) with a spheroid receiver (Gradient Blue‐Red). Based on Cederquist, G.Y., Asciolla, J.J., Tchieu, J. et al. Specification of positional identity in forebrain organoids. Nat Biotechnol 37, 436–444 (). (e) Schematisation of the embryonic neurulation stage, colour coded with: (Green) neural progenitors, (Red) neural crest, (Blue) epidermis and (Orange) the placord. At the centre of the green neuroepithelial cells, the yellow‐black circles indicate the lumen and the apical‐side. Adapted from Haremaki, T., Metzger, J. J., Rito, T., Ozair, M. Z., Etoc, F., & Brivanlou, A. H. (). Self‐organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment. Nature Biotechnology. (f) Self‐organized neural progenitors oriented in a central lumen structure in micropattern, named ‘cerebroid’. The same colour code of panel e. (g) Self‐organized neural and nonneural ectodermal lineages in micropattern, ‘neuruloids’. Neuruloids cytoarchitecture models the in vivo neurulation stage of the ectodermal lineages. The same colour code of panel e. Adapted from Haremaki, T., Metzger, J. J., Rito, T., Ozair, M. Z., Etoc, F., & Brivanlou, A. H. (). Self‐organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment. Nature Biotechnology.
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Further Reading

Cederquist GY, Asciolla JJ, Tchieu J, et al. (2019) Specification of positional identity in forebrain organoids. Nature Biotechnology. DOI: 10.1038/s41587‐019‐0085‐3.

Chambers SM, Fasano CA, Papapetrou EP, et al. (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnology. DOI: 10.1038/nbt.1529.

Eiraku M, Takata N, Ishibashi H, et al. (2011) Self‐organizing optic‐cup morphogenesis in three‐dimensional culture. Nature. DOI: 10.1038/nature09941.

Haremaki T, Metzger JJ, Rito T, et al. (2019) Self‐organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment. Nature Biotechnology. DOI: 10.1038/s41587‐019‐0237‐5.

Hemmati‐Brivanlou A and Melton DA (1992) A truncated activin receptor inhibits mesoderm induction and formation of axial structures in Xenopus embryos. Nature. DOI: 10.1038/359609a0.

Lancaster MA, Renner M, Martin CA, et al. (2013) Cerebral organoids model human brain development and microcephaly. Nature. DOI: 10.1038/nature12517.

Sasai Y, Lu B, Steinbeisser H, et al. (1994) Xenopus chordin: a novel dorsalizing factor activated by organizer‐specific homeobox genes. Cell. DOI: 10.1016/0092‐8674(94)90068‐X.

Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. DOI: 10.1016/j.cell.2006.07.024.

Wilson PA and Hemmati‐Brivanlou A (1995) Induction of epidermis and inhibition of neural fate by Bmp‐4. Nature. DOI: 10.1038/376331a0.

Yang Y, Liu B, Xu J, et al. (2017) Derivation of pluripotent stem cells with in vivo embryonic and extraembryonic potency. Cell. DOI: 10.1016/j.cell.2017.02.005.

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De Santis, R, and Brivanlou, Ali H(Oct 2020) From Neural Induction in Frogs to Human Brains on Chips. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029209]