Reconstructing human pancreatic differentiation by mapping specific cell populations during development

  1. Cyrille Ramond
  2. Nicolas Glaser
  3. Claire Berthault
  4. Jacqueline Ameri
  5. Jeannette Schlichting Kirkegaard
  6. Mattias Hansson
  7. Christian Honoré
  8. Henrik Semb
  9. Raphaël Scharfmann  Is a corresponding author
  1. Cochin Institute, France
  2. Faculty of Health Sciences, University of Copenhagen, Denmark
  3. Novo Nordisk A/S, Denmark

Abstract

Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7 weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2+ population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3, a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Cyrille Ramond

    INSERM U1016, Cochin Institute, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Nicolas Glaser

    INSERM U1016, Cochin Institute, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Claire Berthault

    INSERM U1016, Cochin Institute, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Jacqueline Ameri

    The Danish Stem Cell Center (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeannette Schlichting Kirkegaard

    Department of Islet and Stem Cell Biology, Novo Nordisk A/S, Måløv, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Mattias Hansson

    Global Research External Affairs, Novo Nordisk A/S, Måløv, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian Honoré

    Department of Islet and Stem Cell Biology, Novo Nordisk A/S, Måløv, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  8. Henrik Semb

    The Danish Stem Cell Center (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  9. Raphaël Scharfmann

    INSERM U1016, Cochin Institute, Paris, France
    For correspondence
    raphael.scharfmann@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7619-337X

Funding

European commition's seventh framework program (602587)

  • Raphaël Scharfmann

Innovative medicines initiative (115439)

  • Raphaël Scharfmann

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Ramond et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,667
    views
  • 697
    downloads
  • 51
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Cyrille Ramond
  2. Nicolas Glaser
  3. Claire Berthault
  4. Jacqueline Ameri
  5. Jeannette Schlichting Kirkegaard
  6. Mattias Hansson
  7. Christian Honoré
  8. Henrik Semb
  9. Raphaël Scharfmann
(2017)
Reconstructing human pancreatic differentiation by mapping specific cell populations during development
eLife 6:e27564.
https://doi.org/10.7554/eLife.27564

Share this article

https://doi.org/10.7554/eLife.27564

Further reading

    1. Developmental Biology
    Anastasiia Lozovska, Ana Casaca ... Moises Mallo
    Research Article

    During the trunk to tail transition the mammalian embryo builds the outlets for the intestinal and urogenital tracts, lays down the primordia for the hindlimb and external genitalia, and switches from the epiblast/primitive streak (PS) to the tail bud as the driver of axial extension. Genetic and molecular data indicate that Tgfbr1 is a key regulator of the trunk to tail transition. Tgfbr1 has been shown to control the switch of the neuromesodermal competent cells from the epiblast to the chordoneural hinge to generate the tail bud. We now show that in mouse embryos Tgfbr1 signaling also controls the remodeling of the lateral plate mesoderm (LPM) and of the embryonic endoderm associated with the trunk to tail transition. In the absence of Tgfbr1, the two LPM layers do not converge at the end of the trunk, extending instead as separate layers until the caudal embryonic extremity, and failing to activate markers of primordia for the hindlimb and external genitalia. The vascular remodeling involving the dorsal aorta and the umbilical artery leading to the connection between embryonic and extraembryonic circulation was also affected in the Tgfbr1 mutant embryos. Similar alterations in the LPM and vascular system were also observed in Isl1 null mutants, indicating that this factor acts in the regulatory cascade downstream of Tgfbr1 in LPM-derived tissues. In addition, in the absence of Tgfbr1 the embryonic endoderm fails to expand to form the endodermal cloaca and to extend posteriorly to generate the tail gut. We present evidence suggesting that the remodeling activity of Tgfbr1 in the LPM and endoderm results from the control of the posterior PS fate after its regression during the trunk to tail transition. Our data, together with previously reported observations, place Tgfbr1 at the top of the regulatory processes controlling the trunk to tail transition.

    1. Developmental Biology
    2. Neuroscience
    Odessa R Yabut, Jessica Arela ... Samuel J Pleasure
    Research Article

    Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases and that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.