Induction of neural crest stem cells from Bardet-Biedl Syndrome patient derived hiPSCs

William Barclay Barrell, John Noel Griffin, Jessica-Lily Harvey, HipSci Consortium, Davide Danovi, Philip Beales, Agamemnon Grigoriadis, Karen Jasmine Liu

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Neural crest cells arise in the embryo from the neural plate border and migrate throughout the body, giving rise to many different tissue types such as bones and cartilage of the face, smooth muscles, neurons and melanocytes. While studied extensively in animal models, neural crest development and disease have been poorly described in human due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells (hiPSCs) have become easier to generate, and several streamlined protocols have enabled robust differentiation of hiPSCs to the neural crest lineage. Thus, a unique opportunity is offered for modelling neurocristopathies using patient specific stem cell lines. In this work, we make use of hiPSCs derived from patients affected by the Bardet-Biedl Syndrome (BBS) ciliopathy. BBS patients often exhibit subclinical craniofacial dysmorphisms that are likely to be associated with the neural crest-derived facial skeleton. We focus on hiPSCs carrying variants in the BBS10 gene, which encodes a protein forming part of a chaperonin-like complex associated with the cilium. Here, we establish a pipeline for profiling hiPSCs during differentiation toward the neural crest stem cell fate. This can be used to characterise the differentiation properties of the neural crest-like cells. Two different BBS10 mutant lines showed a reduction in expression of the characteristic neural crest gene expression profile. Further analysis of both BBS10 mutant lines highlighted the inability of these mutant lines to differentiate towards a neural crest fate, which was also characterised by a decreased WNT and BMP response. Altogether, our study suggests a requirement for wild-type BBS10 in human neural crest development. In the long term, approaches such as the one we describe will allow direct comparison of disease-specific cell lines. This will provide valuable insights into the relationships between genetic background and heterogeneity in cellular models. The possibility of integrating laboratory data with clinical phenotypes will move us towards precision medicine approaches.
Original languageEnglish
Article number139
JournalFrontiers in Molecular Neuroscience
Publication statusPublished - 21 Jun 2019


  • BBS
  • Bardet–Biedl Syndrome
  • HiPSCs
  • Human induced pluripotent stem cells
  • Neural crest


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