Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling

A Sophie Brumm; Afshan McCarthy; Claudia Gerri; Todd Fallesen; Laura Woods; Riley McMahon; Athanasios Papathanasiou; Kay Elder; Phil Snell; Leila Christie; Patricia Garcia; Valerie Shaikly; Mohamed Taranissi; Paul Serhal; Rabi A Odia; Mina Vasilic; Anna Osnato; Peter J Rugg-Gunn; Ludovic Vallier; Caroline S Hill; Kathy K Niakan

doi:10.1016/j.devcel.2024.10.020

Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling

Dev Cell. 2024 Nov 15:S1534-5807(24)00639-7. doi: 10.1016/j.devcel.2024.10.020. Online ahead of print.

Authors

A Sophie Brumm¹, Afshan McCarthy¹, Claudia Gerri¹, Todd Fallesen², Laura Woods³, Riley McMahon³, Athanasios Papathanasiou⁴, Kay Elder⁴, Phil Snell⁴, Leila Christie⁴, Patricia Garcia⁵, Valerie Shaikly⁵, Mohamed Taranissi⁵, Paul Serhal⁶, Rabi A Odia⁶, Mina Vasilic⁶, Anna Osnato⁷, Peter J Rugg-Gunn⁸, Ludovic Vallier⁹, Caroline S Hill¹⁰, Kathy K Niakan¹¹

Affiliations

¹ Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
² Crick Advanced Light Microscopy, The Francis Crick Institute, London NW1 1AT, UK.
³ Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
⁴ Bourn Hall Clinic, Bourn, Cambridge CB23 2TN, UK.
⁵ Assisted Reproduction and Gynaecology Centre, London W1G 6LP, UK.
⁶ Centre for Reproductive and Genetic Health, London W1W 5QS, UK.
⁷ Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Development and Regeneration, University of Leuven, Leuven 3000, Belgium.
⁸ Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
⁹ Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.
¹⁰ Developmental Signalling Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
¹¹ Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: [email protected].

PMID: 39561779
DOI: 10.1016/j.devcel.2024.10.020

Abstract

The human blastocyst contains the pluripotent epiblast from which human embryonic stem cells (hESCs) can be derived. ACTIVIN/NODAL signaling maintains expression of the transcription factor NANOG and in vitro propagation of hESCs. It is unknown whether this reflects a functional requirement for epiblast development in human embryos. Here, we characterized NODAL signaling activity during pre-implantation human development. We showed that NANOG is an early molecular marker restricted to the nascent human pluripotent epiblast and was initiated prior to the onset of NODAL signaling. We further demonstrated that expression of pluripotency-associated transcription factors NANOG, SOX2, OCT4, and KLF17 were maintained in the epiblast in the absence of NODAL signaling activity. Genome-wide transcriptional analysis showed that NODAL signaling inhibition did not decrease NANOG transcription or impact the wider pluripotency-associated gene regulatory network. These data suggest differences in the signaling requirements regulating pluripotency in the pre-implantation human epiblast compared with existing hESC culture.

Keywords: BMP signaling; NANOG; NODAL signaling; epiblast; human embryo; pluripotency.