Abstract
Tissue-specific stem cells are considered to have a limited differentiation potential. Recently, this notion was challenged by reports that showed a broader differentiation potential of neural stem cells, in vitro and in vivo, although the molecular mechanisms that regulate plasticity of neural stem cells are unknown. Here, we report that neural stem cells derived from mouse embryonic cortex respond to Lif and serum in vitro and undergo epithelial to mesenchymal transition (EMT)-mediated dedifferentiation process within 48 h, together with transient upregulation of pluripotency markers and, more notably, upregulation of mesendoderm genes, Brachyury (T) and Sox17. These induced putative mesendoderm cells were injected into early gastrulating chick embryos, which revealed that they integrated more efficiently into mesoderm and endoderm lineages compared to non-induced cells. We also found that TGFβ and Jak/Stat pathways are necessary but not sufficient for the induction of mesendodermal phenotype in neural stem cells. These results provide insights into the regulation of plasticity of neural stem cells through EMT. Dissecting the regulatory pathways involved in these processes may help to gain control over cell fate decisions.
Highlights
Major cell fate decisions occur early in embryonic development when all three germ layers are established during gastrulation
Neural stem cells cultured in serum and Lif display upregulation of pluripotency markers Neurospheres were derived from mouse embryonic cortex at E12.5 and typically expanded for 5 passages in serum-free N2B27 media supplemented with EGF and bFGF
This might be because stem cells may not fully exhibit their full differentiation potential in their confined microenvironment, which becomes evident in an inductive environment in vitro
Summary
Major cell fate decisions occur early in embryonic development when all three germ layers are established during gastrulation. This is achieved at the level of the primitive streak, by epithelial to mesenchymal transitions (EMT), where embryonic epiblast cells lose their typical epithelial character with tight cell-cell junctions and acquire a mesenchymal morphology with loose cell-cell contacts and high motility [1,2,3,4]. During further stages of development cells within the germ layers undergo several rounds of EMT and/or its opposite, mesenchymal to epithelial transition (MET) to form various tissues and organs [4]. There is emerging evidence indicating that EMT as well as MET have a pivotal role in regulating cell plasticity and re-establishing tissue integrity, which occurs during wound healing and regeneration in adults [15,16]
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