Notch signaling regulates neural crest differentiation from human pluripotent stem cells

Abstract

Neural crest (NC) cells are specified at the border of neural plate and epiderm. They are capable of differentiating into various somatic cell types, including craniofacial and peripheral nerve tissues. Notch signaling plays significant roles during neurogenesis; however, its function during human NC development is poorly understood. Here, we generated self-renewing premigratory NC-like cells (pNCCs) from human pluripotent stem cells and investigated the roles of Notch signaling during the NC differentiation. pNCCs expressed various NC specifier genes, including SLUG, SOX10 and TWIST1, and were able to differentiate into most NC derivatives. Blocking Notch signaling during the pNCC differentiation suppressed the expression of NC specifier genes. In contrast, ectopic expression of activated Notch1 intracellular domain (NICD1) augmented the expression of NC specifier genes, and NICD1 was found to bind at their promoter regions. Notch activity was also required for the maintenance of premigratory NC state, and suppression of Notch led to generation of NC-derived neurons. Taken together, we provide a protocol for the generation of pNCCs, and show that Notch signaling regulates the formation, migration and differentiation of NC from hPSCs.

Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

“…In self-renewing pre-migratory NCCs induced from human pluripotent stem cells, Noisa et al observed that Notch increases the expression of neural-crest-specifier genes ( SLUG or SNAIL2, SOX10 , and TWIST1 ) (Noisa et al, 2014) Moreover, Notch is then a brake of NCCs migration and the inhibition of Notch signaling is followed by a neuronal differentiation of these cells. Using in vitro and in vivo models, Morisson et al demonstrated that Notch inhibits NCCs neuronal differentiation and activates the glial fate, mainly the Schwann cell phenotype (Morrison et al, 2000a,b) but not the satellite cells, the teloglia of somatic motor nerve terminals or the enteric glia (reviewed in Kipanyula et al, 2014).…”

Therapeutically Targeting Epigenetic Regulation of Cancer Stem Cells

“…Subsequently, Notch signaling has been observed in several types of SC and CSC and is a key area of CSC-targeting research [63]. The principle Notch target genes are the "Hes" and "Hey" gene families, which control SC SR and cell fate decisions during differentiation in many adult tissues, often via regulation of Nanog [65]. Notch signaling facilitates cell to cell communication, where "Jagged" and "Delta" receptors on one cell interact with Notch transmembrane receptors on an adjacent cell.…”

“…Notch signaling is a simple pathway containing no secondary messengers or cascade. Notch signaling is primarily known for maintaining SC pools in adult tissues and determining cell fate decisions in the developing embryo [65]. This interaction results in cleavage of the "Notch intercellular domain" (NICD), which translocates to the nucleus of the cell to regulate target genes [64].…”

Neural crest cells: From developmental biology to clinical interventions

“…B : Modulation of WNT and SMAD signaling allows efficient derivation of migratory neural crest cells from hPSCs at day 10 of the induction (Menendez et al, ). C : Modification of the previous protocol to modulate WNT and BMP signaling in N2B27 medium permits hPSCs to convert into premigratory neural crest‐like cells at day 10 of the induction (Noisa et al, ). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.…”

“…The cells were premigratory neural crest cells, but phenotypically shifted to p75/HNK1‐positive migratory cells upon application of FGF8 and Notch inhibitor. The premigratory neural crest‐like cells can be clonally expanded and differentiated to neural crest derivatives, such as peripheral sensory neurons, adipocytes, chondrocytes, and osteocytes (Noisa et al, ). These pre‐migratory neural crest‐like cells allow studying the early events of human neural crest lineage commitment and also neural crest fate specification.…”