Induction of neural crest stem vells from Bardet–Biedl Syndrome patient derived hiPSCs
MetadataShow full item record
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 humans 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 modeling 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 characterize 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 toward a neural crest fate, which was also characterized 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 toward precision medicine approaches.
Barrell , W B , Griffin , J N , Harvey , J-L , HipSci Consortium , Danovi , D , Beales , P , Grigoriadis , A E & Liu , K J 2019 , ' Induction of neural crest stem vells from Bardet–Biedl Syndrome patient derived hiPSCs ' Frontiers in Molecular Neuroscience , vol. 12 , 139 . https://doi.org/10.3389/fnmol.2019.00139
Frontiers in Molecular Neuroscience
Copyright © 2019 Barrell, Griffin, Harvey, HipSci Consortium, Danovi, Beales, Grigoriadis and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DescriptionWB was supported by the EPSRC (1524932), KL was supported by BBSRC (BB/R015953/1), BHF (PG/17/79/33313), and MRC (MR/R014302/1). AG was supported by the Bone Cancer Research Trust. This study makes use of data generated by the HipSci Consortium, funded by The Wellcome Trust and the MRC.
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.