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An Epiblast Stem Cell derived multipotent progenitor population for axial extension

Shlomit Edri, Penelope Hayward, Peter Baillie-Johnson, Benjamin Steventon, Alfonso Martinez Arias

Preprint posted on 4 January 2018 https://www.biorxiv.org/content/early/2018/01/04/242461

Article now published in Development at http://dx.doi.org/10.1242/dev.168187

Stabilisation of self-renewing Neuro-Mesodermal Progenitors in vitro by using EpiSC as a starting material.

Selected by Pierre Osteil

Categories: developmental biology

Background:

Cells in the early embryo go through a journey of specialisation to achieve more complex functions. During the early days of development, one critical step, called gastrulation, is the establishment of the three primitive germ layers at the stem of different tissue and organs: the ectoderm – skin and brain -, the mesoderm – blood and muscle – and the endoderm – gut, lung, liver and other organs. Among other outcomes of gastrulation is the generation of bi-potential progenitors that contribute to spinal cord (ectoderm) elongation and to paraxial mesoderm: so called Neuro-Mesodermal Progenitors (NMPs). While it is straightforward to observe Xenopus or fish embryos developing live, mammalian development studies face the issue of in-utero development: collecting embryos for experiment would impair their development. To allow the study of NMPs in mammals, developmental biologists have therefore turned to embryonic stem cell systems.

 

The Paper

In this study, Edri et al. generated for the first time self-renewing NMPs. Indeed, previous studies have reported the establishment of NMPs capable of colonizing mouse embryos, but this NMP state was transitory (Gouti 2014). Here, the authors were able to stabilise them and show that they could, upon grafting into chick embryos, contribute to presomitic and neural tissues of chick embryos (Figure: NMPs in red). The self renewing feature of these NMPs is an important improvement for the field as the cells can now be grown in vitro for longer and be studied more extansively.

The authors also demonstrate, by a comparison of transcriptomic datasets, that every published NMPs differentiation protocols inevitably drive the cells through a common multipotent state.

Image reproduced from Edri et al., 2018 Fig 7A

 

Why did I choose this article?

Since 2007, epiblast stem cells (EpiSCs), a type of pluripotent stem cells derived from gastrulating mouse embryos (rather than blastocysts – the origin for embryonic stem cells; ESCs) have been available. Edri and colleagues demonstrate here that, establishing NMPs from EpiSCs (Epi-NMPs) is more efficient than from ESCs. To achieve that, the authors adapted a protocol previously published for differentiation of human ESCs to similar progenitors (Lippmann 2015). I found that this approach makes a lot of sense as EpiSCs are known to be equivalent to the epiblast of E7.0 embryos (Kojima 2014) when NMPs are likely to emerge. They highlight the importance of choosing the appropriate starting material for differentiation protocols.

 

“EpiSCs are closer to human ESCs than mouse ESCs and therefore this observation emphasizes the possible importance of the initial state of the population for the paths and outcomes of differentiation”

 

Open questions

  1. To constitute a more robust evidence of the bi-potency feature of these cells, it will be important to demonstrate the isolation and differentiation of one NMP cell into both tissues.
  2. Ultimately, the developmental field would ask if these cells could contribute to a mouse embryo, as was shown by Gouti and colleagues.
  3. The authors mentioned that their Epi-NMPs display a “limited but robust self-renewal” It would be worthwhile to investigate signalling activities in order to retain this property and being able to grow them for longer.

 

Related research:

Gouti, M., Tsakiridis, A., Wymeersch, F. J., Huang, Y., Kleinjung, J., Wilson, V. and Briscoe, J. (2014). In vitro generation of neuromesodermal progenitors reveals distinct roles for wnt signalling in the specification of spinal cord and paraxial mesoderm identity. PLoS biology 12, e1001937.

Lippmann, E. S., Williams, C. E., Ruhl, D. A., Estevez-Silva, M. C., Chapman, E. R., Coon, J. J. and Ashton, R. S. (2015). Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm. Stem cell reports 4, 632-644.

Kojima, Y., Kaufman-Francis, K., Studdert, J. B., Steiner, K. A., Power, M. D., Loebel, D. A., Jones, V., Hor, A., de Alencastro, G., Logan, G. J., et al. (2014). The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14, 107-120.

 

Tags: episc, gastrulation, mouse, nmp

Posted on: 18 February 2018 , updated on: 8 March 2018

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Shlomit Edri shared

As you wrote, this is the first report of self renewing NMPs in vitro, which is something missing in previous studies (including Gouti et al. 2014 and our own work of Turner et al. 2014). Moreover, we would like to emphasize the importance of the discovery that each protocol leads to a multipotent population that, in addition to NMPs, will also give rise to progenitors for LPM and IM and allantois.

Answering your open questions:

1. Isolation of one cell of NMP in culture might be a difficult task, since as we know EpiSCs are not clonal, meaning they can’t exist as one cell but rather prefer to be together with others. Furthermore, in our paper we demonstrated the difference in the number of cells between the different protocols and the importance of seeding the right number of cells (in Epi-NMP and its derivatives protocols we seeds high number of cells in comparison to the other protocols). Nonetheless we have been able to clone them at low frequency (unpublished results).

 

2. It would be the ultimate test to examine the ability of these cells and we are thinking about this possibility but as you know not many people can do these experiments. Nonetheless, we feel that the chicken assay works (see also Peter Baillie-Johnson and colleagues preprint in bioRxiv: https://www.biorxiv.org/content/early/2018/01/08/243980)

 

3. We investigated the Epi-NMP in different signals environment, which we mentioned in the paper, and in other techniques more in the mechanics sense, that might help us maintain these cell in a robust way in culture.

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