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An in vitro stem cell model of human epiblast and yolk sac interaction

Mackinlay, Kirsty M. L. and Weatherbee, Bailey A. T. and Souza Rosa, Viviane and Handford, Charlotte E. and Hudson, George and Coorens, Tim and Pereira, Lygia V. and Behjati, Sam and Vallier, Ludovic and Shahbazi, Marta N. and Zernicka-Goetz, Magdalena (2021) An in vitro stem cell model of human epiblast and yolk sac interaction. eLife, 10 . Art. No. e63930. ISSN 2050-084X. PMCID PMC8370770. doi:10.7554/elife.63930.

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Human embryogenesis entails complex signalling interactions between embryonic and extra-embryonic cells. However, how extra-embryonic cells direct morphogenesis within the human embryo remains largely unknown due to a lack of relevant stem cell models. Here, we have established conditions to differentiate human pluripotent stem cells (hPSCs) into yolk sac-like cells (YSLCs) that resemble the post-implantation human hypoblast molecularly and functionally. YSLCs induce the expression of pluripotency and anterior ectoderm markers in human embryonic stem cells (hESCs) at the expense of mesoderm and endoderm markers. This activity is mediated by the release of BMP and WNT signalling pathway inhibitors, and, therefore, resembles the functioning of the anterior visceral endoderm signalling centre of the mouse embryo, which establishes the anterior-posterior axis. Our results implicate the yolk sac in epiblast cell fate specification in the human embryo and propose YSLCs as a tool for studying post-implantation human embryo development in vitro.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Mackinlay, Kirsty M. L.0000-0001-6276-4274
Weatherbee, Bailey A. T.0000-0002-6825-6278
Hudson, George0000-0003-2506-6965
Behjati, Sam0000-0002-6600-7665
Vallier, Ludovic0000-0002-3848-2602
Shahbazi, Marta N.0000-0002-1599-5747
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Additional Information:© 2021 Mackinlay et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 10 October 2020; Accepted: 03 August 2021; Published: 17 August 2021. The work in the MZG laboratory is supported by grants from the Wellcome Trust (207415/Z/17/Z), the ERC advanced grant (669198), the NIH R01 (HD100456-01A1) grant, the NIH Pioneer Award (DP1 HD104575-01), Open Philanthropy/Silicon Valley Community Foundation, Weston Havens Foundation, and Shurl and Kay Curci Foundation to MZG. KM is a recipient of PhD studentship funding from the BBSRC. BATW is a recipient of a PhD studentship funded by the Gates Cambridge Trust. CEH is the recipient of a PhD studentship funded by The Centre for Trophoblast Research (University of Cambridge). Work in the group of MNS is funded by the Medical Research Council (MRC, award number MC_UP_1201/24) and the European Molecular Biology Organisation (Advanced EMBO fellowship). This research was also supported by the Cambridge NIHR BRC Cell Phenotyping Hub, who we thank for their advice and support in flow cytometry/cell sorting/imaging. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: Kirsty ML Mackinlay, Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing; Bailey AT Weatherbee, Formal analysis, Investigation, Visualization, writing- review and editing; Viviane Souza Rosa, Data curation, Formal analysis, Validation, Investigation; Charlotte E Handford, Investigation, Data curation; George Hudson, Investigation; Tim Coorens, Formal analysis; Lygia V Pereira, Sam Behjati, Supervision; Ludovic Vallier, Resources, Supervision; Marta N Shahbazi, Conceptualization, Resources, Supervision, Investigation, Methodology, Project administration, Writing - review and editing; Magdalena Zernicka-Goetz, Supervision, Writing - review and editing. Ethics: hESC experiments: The UK Stem Cell Bank Steering Committee approved all hESC experiments. All experiments comply with the UK code of Practise for the Use of Human Stem Cell Lines. Mouse embryo work: All national and international guidelines were followed for mouse upkeep. Experiments were approved by the Home Office, reviewed by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB), and were regulated by the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012. Animals were inspected daily and those that showed health concerns were culled by cervical dislocation. Data availability: Raw data is available on EGA at accession number: EGAD00001006056 under the study number EGAS00001003571.
Funding AgencyGrant Number
Wellcome Trust207415/Z/17/Z
European Research Council (ERC)669198
NIHR01 HD100456-01A1
NIHDP1 HD104575-01
Open PhilanthropyUNSPECIFIED
Silicon Valley Community FoundationUNSPECIFIED
Weston Havens FoundationUNSPECIFIED
Shurl and Kay Curci FoundationUNSPECIFIED
Biotechnology and Biological Sciences Research Council (BBSRC)UNSPECIFIED
Gates Cambridge TrustUNSPECIFIED
University of CambridgeUNSPECIFIED
Medical Research Council (UK)MC_UP_1201/24
European Molecular Biology Organization (EMBO)UNSPECIFIED
PubMed Central ID:PMC8370770
Record Number:CaltechAUTHORS:20210930-211337700
Persistent URL:
Official Citation:An in vitro stem cell model of human epiblast and yolk sac interaction. Mackinlay et al. eLife 2021; 10:e63930. DOI:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111136
Deposited By: Tony Diaz
Deposited On:04 Oct 2021 20:29
Last Modified:04 Oct 2021 21:02

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