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 January 04, 2018

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

Selected by Pierre Osteil

Categories: developmental biology


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

Read preprint (No Ratings Yet)

  • 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:


    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.

    Have your say

    Your email address will not be published. Required fields are marked *

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    Polyacrylamide Bead Sensors for in vivo Quantification of Cell-Scale Stress in Zebrafish Development

    Nicole Traeber, Klemens Uhlmann, Salvatore Girardo, et al.

    Selected by Jacky G. Goetz

    millepattes micropeptides are an ancient developmental switch required for embryonic patterning

    Suparna Ray, Miriam I Rosenberg, Hélène Chanut-Delalande, et al.

    Selected by Erik Clark

    Aurora A depletion reveals centrosome-independent polarization mechanism in C. elegans

    Kerstin Klinkert, Nicolas Levernier, Peter Gross, et al.


    Centrosome Aurora A gradient ensures a single PAR-2 polarity axis by regulating RhoGEF ECT-2 localization in C. elegans embryos

    Sachin Kotak, Sukriti Kapoor

    Selected by Giuliana Clemente

    Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

    Amber N Stratman, Olivia M Farrelly, Constantinos M Mikelis, et al.

    Selected by Coert Margadant

    SOL1 and SOL2 Regulate Fate Transition and Cell Divisions in the Arabidopsis Stomatal Lineage

    Abigail R Simmons, Kelli A Davies, Wanpeng Wang, et al.

    Selected by Martin Balcerowicz

    Analysis of the role of Nidogen/entactin in basement membrane assembly and morphogenesis in Drosophila

    Jianli Dai, Beatriz Estrada, Sofie Jacobs, et al.

    Selected by Nargess Khalilgharibi

    Neural crest cells regulate optic cup morphogenesis by promoting extracellular matrix assembly

    Chase Dallas Bryan, Rebecca Lynne Pfeiffer, Bryan William Jones, et al.

    Selected by Ashrifia Adomako-Ankomah


    Simultaneous production of diverse neuronal subtypes during early corticogenesis

    Elia Magrinelli, Robin Jan Wagener, Denis Jabaudon

    Selected by Boyan Bonev


    mRNA localisation in endothelial cells regulates blood vessel sprouting

    Guilherme Costa, Nawseen Tarannum, Shane Herbert

    Selected by Andreas van Impel

    LADL: Light-activated dynamic looping for endogenous gene expression control

    Mayuri Rege, Ji Hun Kim, Jacqueline Valeri, et al.

    Selected by Ivan Candido-Ferreira

    Quantitative, real-time, single cell analysis in tissue reveals expression dynamics of neurogenesis

    Cerys S Manning, Veronica Biga, James Boyd, et al.

    Selected by Teresa Rayon

    The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila

    Selected by Clarice Hong


    Optogenetic dissection of mitotic spindle positioning in vivo

    Lars-Eric Fielmich, Ruben Schmidt, Daniel J Dickinson, et al.

    Selected by Angika Basant


    Excitable RhoA dynamics drive pulsed contractions in the early C. elegans embryo.

    Jonathan B Michaux, Francois B Robin, William M McFadden, et al.

    Selected by Sundar Naganathan

    A transition from SoxB1 to SoxE transcription factors is essential for progression from pluripotent blastula cells to neural crest cells

    Elsy Buitrago-Delgado, Elizabeth Schock, Kara Nordin, et al.

    Selected by Amanda Haage

    Moving beyond P values: Everyday data analysis with estimation plots

    Joses Ho, Tayfun Tumkaya, Sameer Aryal, et al.

    Selected by Gautam Dey