1. Developmental Biology
Download icon

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
Research Article
  • Cited 25
  • Views 2,680
  • Annotations
Cite this article as: eLife 2017;6:e27564 doi: 10.7554/eLife.27564

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.

Reviewing Editor

  1. Neil A Hanley, University of Manchester, United Kingdom

Publication history

  1. Received: April 7, 2017
  2. Accepted: July 17, 2017
  3. Accepted Manuscript published: July 21, 2017 (version 1)
  4. Version of Record published: August 2, 2017 (version 2)

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

  • 2,680
    Page views
  • 586
    Downloads
  • 25
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

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)

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

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

Categories and tags

Research organism

Further reading

    1. Developmental Biology

    Apical contacts stemming from incomplete delamination guide progenitor cell allocation through a dragging mechanism

    Eduardo Pulgar et al.
    Research Article Updated

    The developmental strategies used by progenitor cells to allow a safe journey from their induction place towards the site of terminal differentiation are still poorly understood. Here, we uncovered a mechanism of progenitor cell allocation that stems from an incomplete process of epithelial delamination that allows progenitors to coordinate their movement with adjacent extra-embryonic tissues. Progenitors of the zebrafish laterality organ originate from the superficial epithelial enveloping layer by an apical constriction process of cell delamination. During this process, progenitors retain long-lasting apical contacts that enable the epithelial layer to pull a subset of progenitors on their way to the vegetal pole. The remaining delaminated cells follow the movement of apically attached progenitors by a protrusion-dependent cell-cell contact mechanism, avoiding sequestration by the adjacent endoderm, ensuring their collective fate and allocation at the site of differentiation. Thus, we reveal that incomplete delamination serves as a cellular platform for coordinated tissue movements during development.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine

    Multiscale analysis reveals that diet-dependent midgut plasticity emerges from alterations in both stem cell niche coupling and enterocyte size

    Alessandro Bonfini et al.
    Research Article

    The gut is the primary interface between an animal and food, but how it adapts to qualitative dietary variation is poorly defined. We find that the Drosophila midgut plastically resizes following changes in dietary composition. A panel of nutrients collectively promote gut growth, which sugar opposes. Diet influences absolute and relative levels of enterocyte loss and stem cell proliferation, which together determine cell numbers. Diet also influences enterocyte size. A high sugar diet inhibits translation and uncouples ISC proliferation from expression of niche-derived signals but, surprisingly, rescuing these effects genetically was not sufficient to modify diet's impact on midgut size. However, when stem cell proliferation was deficient, diet's impact on enterocyte size was enhanced, and reducing enterocyte-autonomous TOR signaling was sufficient to attenuate diet-dependent midgut resizing. These data clarify the complex relationships between nutrition, epithelial dynamics, and cell size, and reveal a new mode of plastic, diet-dependent organ resizing.

    1. Developmental Biology
    2. Physics of Living Systems

    Cost-precision trade-off relation determines the optimal morphogen gradient for accurate biological pattern formation

    Yonghyun Song, Changbong Hyeon
    Research Article Updated

    Spatial boundaries formed during animal development originate from the pre-patterning of tissues by signaling molecules, called morphogens. The accuracy of boundary location is limited by the fluctuations of morphogen concentration that thresholds the expression level of target gene. Producing more morphogen molecules, which gives rise to smaller relative fluctuations, would better serve to shape more precise target boundaries; however, it incurs more thermodynamic cost. In the classical diffusion-depletion model of morphogen profile formation, the morphogen molecules synthesized from a local source display an exponentially decaying concentration profile with a characteristic length λ. Our theory suggests that in order to attain a precise profile with the minimal cost, λ should be roughly half the distance to the target boundary position from the source. Remarkably, we find that the profiles of morphogens that pattern the Drosophila embryo and wing imaginal disk are formed with nearly optimal λ. Our finding underscores the cost-effectiveness of precise morphogen profile formation in Drosophila development.