Are NMPs Stem Cells?

NMPs clearly have a great degree of plasticity, giving rise to both neural ectoderm and mesoderm, but it is not clear whether they fit the definition of a stem cell, with the ability to indefinitely self-renew, or are rather a progenitor cell-type that have limited capacity to self-renew. Experiments in amniotes suggest that they are stem cells based on serial transplantations. Cells from the tailbud of chick or mouse embryos were removed and transplanted into younger embryos, and the host embryos were then allowed to develop to later tailbud stages, and the procedure was repeated (Cambray and Wilson, 2002; McGrew et al., 2008; Tam and Tan, 1992). In these experiments, tailbud cells self-renew and contribute to somites along the body axis over several serial transplants. These results suggest that the cells giving rise to the somites are stem cells and have the potential to self-renew their undifferentiated population while simultaneously giving rise to differentiated cells of the somites. Similar experiments have not been performed in zebrafish or Xenopus embryos, but evidence from zebrafish indicates that NMPs rarely divide, and instead are arrested in the G2 phase of the cell cycle at post-gastrulation stages (Bouldin et al., 2014). In the absence of significant self-renewal, NMPs in zebrafish fit better under the definition of a progenitor cell. In the zebrafish, as NMPs are induced to become mesoderm, they undergo a synchronous cell division event, which acts as a transit- amplifying step to increase the number of cells contributing to the somites (Bouldin et ah, 2014).

In vitro-derived NMPs exhibit stem cell-like properties. Mouse NMPs can be efficiently induced in culture from epiblast stem cells (and can also be induced from embryonic stem cells) through the addition of FGF and the GSK-3 inhibitor Chiron, which activates canonical Wnt signaling (Edri et ah, 2019a; Gouti et ah, 2014; Tsakiridis and Wilson, 2015; Turner et ah, 2014). Cultured NMPs can self-renew, but over several passages begin to differentiate, with a tendency to become neural tissue (Edri et ah, 2019a). Mouse NMPs exist adjacent to an embryonic structure called the node, which emits signals to neighboring cells. When NMPs are induced from epiblast stem cells, node-like cells are also generated in the culture (Edri et ah, 2019b). These node-like cells are depleted over time, corresponding to the loss of self-renewal among the NMPs. When cultured NMPs are passaged and then replenished with node-like cells, this extends their undifferentiated and self-renewal state (Edri et ah, 2019b). Thus, when in vitro-derived NMPs are cultured in an environment that mimics their native in vivo environment, they also display stem cell-like properties. These results may also explain the sustained renewal of NMPs in the amniote serial transplant experiments (Cambray and Wilson, 2002; McGrew et ah, 2008; Tam and Tan, 1992), as transplanting the cells to earlier stage embryos ensure that they are continuously exposed to neighboring node cells.

 
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