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Pluripotent Stem Cell-derived Neuruloids - A New Approach to Developmental Analysis and Disease Modeling

Review of “Self-organizing neuruloids model developmental aspects of Huntington’s disease in the ectodermal compartment” from Cell Stem Cell by Stuart P. Atkinson

The study of neurulation, a critical developmental transition that gives rise to different ectodermal derivatives [1], has allowed researchers to guide the differentiation of human pluripotent stem cells (hPSCs) towards distinct ectodermal lineages in vitro [2, 3]. While we understand that transforming growth factor (TGF)-β inhibition, bone morphogenic protein (BMP) signaling, and Wnt and fibroblast growth factor (FGF) signaling synergize to promote neurulation, we know little regarding how their spatial and temporal expression contributes to embryogenesis.

To understand neurulation at a deeper level, researchers led by Ali H. Brivanlou (The Rockefeller University, New York, USA) describe the application of micropatterning culture technology to create structures named “neuruloids” that recapitulate early human neurulation [4]. Haremaki et al. hope that this approach will provide insight into early human development and into a range of poorly understood human genetic diseases and pediatric cancers that involve the ectodermal compartment.

As described in their Nature Biotechnology article, the authors induced the differentiation of hPSCs into self-organizing neuruloid colonies using micropatterned culture substrates and sequential dual-SMAD inhibition and BMP4 stimulation. Neuruloids contained four ectodermal cell types (neural progenitors, neural crest, sensory placode, and epidermis) in a spatial arrangement that mimicked the ectodermal organization observed in vivo at neurulation stages This approach generated large numbers of highly similar neuruloids to which the authors applied single-cell transcriptomics to explore the spatial and temporal nature of fate specification. 

Interestingly, this analysis provided for the discovery of sets of early embryonic markers for each human lineage, and the team identified over 100 genes with an expression pattern specific to each population. Of note, while each pluripotent stem cell line employed generated the same four ectodermal cell types, the relative proportions of the primary cell types in neuruloids varied. Furthermore, the gene expression data placed neuruloids at the neural tube closure stages (days 21–25), thereby providing insight into the earliest stages of human development.

Finally, the authors highlighted the potential for neuruloid in the developmental study of complex human neurodegenerative disease aspects by employing isogenic Huntington’s disease human embryonic stem cells and deep neural network analysis. Excitingly, the presence of the mutant huntingtin protein prompted the highly reproducible development of specific alterations to neuruloid morphology that may be due to a polarization defect in the neuroepithelial cells prompted by an impairment in the actin-mediated tissue organization mechanism. 

While the authors highlight neuruloids as an exciting new means to study human ectodermal development at multiple levels, they also propose the application of neuruloids derived from disease-specific hPSCs in phenotypic drug screens that may lead to the development of novel therapeutic approaches.

For more on the enormous promise of hPSC-derived neuruloids, stay tuned to the Stem Cells Portal!



  1. Ozair MZ, Kintner C, and Brivanlou AH, Neural induction and early patterning in vertebrates. Wiley Interdisciplinary Reviews: Developmental Biology 2013;2:479-498.
  2. Dincer Z, Piao J, Niu L, et al., Specification of Functional Cranial Placode Derivatives from Human Pluripotent Stem Cells. Cell Reports 2013;5:1387-1402.
  3. Tchieu J, Zimmer B, Fattahi F, et al., A Modular Platform for Differentiation of Human PSCs into All Major Ectodermal Lineages. Cell Stem Cell 2017;21:399-410.e7.
  4. Haremaki T, Metzger JJ, Rito T, et al., Self-organizing neuruloids model developmental aspects of Huntington’s disease in the ectodermal compartment. Nature Biotechnology 2019;37:1198-1208.