Abstract
SummaryNeural crest cells (NCCs) contribute to several tissues during embryonic development. NCC formation depends on activation of tightly regulated molecular programs at the neural plate border (NPB) region, which initiate NCC specification and epithelial-to-mesenchymal transition (EMT). Although several approaches to investigate NCCs have been devised, these early events of NCC formation remain largely unknown in humans, and currently available cellular models have not investigated EMT. Here, we report that the E6 neural induction protocol converts human induced pluripotent stem cells into NPB-like cells (NBCs), from which NCCs can be efficiently derived. NBC-to-NCC induction recapitulates gene expression dynamics associated with NCC specification and EMT, including downregulation of NPB factors and upregulation of NCC specifiers, coupled with other EMT-associated cell-state changes, such as cadherin modulation and activation of TWIST1 and other EMT inducers. This strategy will be useful in future basic or translational research focusing on these early steps of NCC formation.
Highlights
Neural crest cells (NCCs) are a multipotent cell population that plays pivotal roles in vertebrate embryonic development
In late-blastula stages, intermediate BMP levels specify cells residing between the prospective neural and non-neural ectoderm into the neural plate border (NPB), a broad competence domain that contributes to formation of the neural tube, neural crest (NC), and the preplacodal and non-neural ectoderm (Pla and Monsoro-Burq, 2018)
We found that key NPB specifiers TFAP2A, DLX5, PAX3, ZIC1, and MSX2 were upregulated on day 4 (Figure 1C), along with other NPB factors SP5, SMURF1, CKIP1, and SIX1 (Maharana and Schlosser, 2018; Park et al, 2013; Piacentino and Bronner, 2018) (Figure 1D)
Summary
Neural crest cells (NCCs) are a multipotent cell population that plays pivotal roles in vertebrate embryonic development. In late-blastula stages, intermediate BMP levels specify cells residing between the prospective neural and non-neural ectoderm into the neural plate border (NPB), a broad competence domain that contributes to formation of the neural tube, neural crest (NC), and the preplacodal and non-neural ectoderm (Pla and Monsoro-Burq, 2018). Disturbances in any of the above steps may impair NC development and result in several human health conditions. These include congenital disorders arising from defects in NC derivatives, such as craniofacial syndromes, pigmentation disorders, Hirschprung disease, and others, and aggressive cancers of NC origin, such as neuroblastoma and melanoma (Vega-Lopez et al, 2018). Most of them do not include an NPB stage, and EMT has been extensively modeled in human cells in the context of cancer (Yang et al, 2020), currently there is still no in vitro approach describing human NC EMT
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