BMP signaling induces visceral endoderm differentiation of XEN cells and parietal endoderm
Open accessAbstract
The extraembryonic endoderm of mammals is essential for nutritive support of the fetus and patterning of the early embryo. Visceral and parietal endoderm are major subtypes of this lineage with the former exhibiting most, if not all, of the embryonic patterning properties. Extraembryonic endoderm (XEN) cell lines derived from the primitive endoderm of mouse blastocysts represent a cell culture model of this lineage, but are biased towards parietal endoderm in culture and in chimeras. In an effort to promote XEN cells to adopt visceral endoderm character we have mimicked different aspects of the in vivo environment. We found that BMP signaling promoted a mesenchymal-to-epithelial transition of XEN cells with up-regulation of E-cadherin and down-regulation of vimentin. Gene expression analysis showed the differentiated XEN cells most resembled extraembryonic visceral endoderm (exVE), a subtype of VE covering the extraembryonic ectoderm in the early embryo, and during gastrulation it combines with extraembryonic mesoderm to form the definitive yolk sac. We found that laminin, a major component of the extracellular matrix in the early embryo, synergised with BMP to promote highly efficient conversion of XEN cells to exVE. Inhibition of BMP signaling with the chemical inhibitor, Dorsomorphin, prevented this conversion suggesting that Smad1/5/8 activity is critical for exVE induction of XEN cells. Finally, we show that applying our new culture conditions to freshly isolated parietal endoderm (PE) from Reichert's membrane promoted VE differentiation showing that the PE is developmentally plastic and can be reprogrammed to a VE state in response to BMP. Generation of visceral endoderm from XEN cells uncovers the true potential of these blastocyst-derived cells and is a significant step towards modelling early developmental events ex vivo.
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emVE represents a specialized variant of exVE, perhaps modulating a transcriptional program in response to stimuli such as BMP or Nodal.
“Differential expression between bulk RNA sequenced E7.5 exVE and emVE populations suggested that emVE represents a specialized variant of exVE (Extended Data Fig. 7d), perhaps modulating a transcriptional program in response to stimuli, such as BMP or Nodal38–40.”
From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [38]
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- Authors
- Paca, A., Séguin, C. A., Clements, M., Ryczko, M., Rossant, J., Rodriguez, T. A., & Kunath, T.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Hospital for Sick Children (CA)
- Hammersmith Hospital (GB)
- Corresponding author
- Kunath, Tilo
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 361
- Issue
- 1
- Pages
- 90-102
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W2119250654
- Cited by
- 87
- References
- 103
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 563 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Pfizer
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- BMP signaling, parietal endoderm, extraembryonic endoderm, mesenchymal-epithelial transition, E-cadherin, vimentin, laminin, Smad1/5/8, compound C, Reichert's membrane, yolk sac, developmental plasticity
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Endoderm, Epithelial Cells, Extracellular Matrix, Flow Cytometry, Fluorescent Antibody Technique, Laminin, Mesoderm, Pyrazoles, Pyrimidines, Vimentin, Signal Transduction, Cadherins, Gene Expression Regulation, Developmental, Cell Culture Techniques, Reverse Transcriptase Polymerase Chain Reaction, Microarray Analysis, Mice, Bone Morphogenetic Protein 4
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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