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  3. Modeling human extraembryonic mesoderm cells using naive pluripotent stem cells

Modeling human extraembryonic mesoderm cells using naive pluripotent stem cells

  • Cell Stem Cell. 2022 Sep 1;29(9):1346-1365.e10. doi: 10.1016/j.stem.2022.08.001.
Thi Xuan Ai Pham 1,  Amitesh Panda 1,  Harunobu Kagawa 2,  San Kit To 1,  Cankat Ertekin 1,  Grigorios Georgolopoulos 1,  Sam S F A van Knippenberg 1,  Ryan Nicolaas Allsop 1,  Alexandre Bruneau 3,  Jonathan Sai-Hong Chui 1,  Lotte Vanheer 1,  Adrian Janiszewski 1,  Joel Chappell 1,  Michael Oberhuemer 1,  Raissa Songwa Tchinda 1,  Irene Talon 1,  Sherif Khodeer 1,  Janet Rossant 4,  Frederic Lluis 1,  Laurent David 5,  Nicolas Rivron 2,  Bradley Philip Balaton 6,  Vincent Pasque 7
Affiliations

Affiliations

  • 1 Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single-cell Omics (LISCO), KU Leuven-University of Leuven, 3000 Leuven, Belgium.
  • 2 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria.
  • 3 Nantes Université, CHU Nantes, Inserm, CR2TI, UMR 1064, F-44000, Nantes, France.
  • 4 Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5V 0B1, Canada.
  • 5 Nantes Université, CHU Nantes, Inserm, CR2TI, UMR 1064, F-44000, Nantes, France; Nantes Université, CHU Nantes, Inserm, CNRS, BioCore, F-44000 Nantes, France.
  • 6 Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single-cell Omics (LISCO), KU Leuven-University of Leuven, 3000 Leuven, Belgium. Electronic address: bradley.balaton@kuleuven.be.
  • 7 Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single-cell Omics (LISCO), KU Leuven-University of Leuven, 3000 Leuven, Belgium. Electronic address: vincent.pasque@kuleuven.be.
PMID: 36055191 DOI: 10.1016/j.stem.2022.08.001
Abstract

A hallmark of primate postimplantation embryogenesis is the specification of extraembryonic mesoderm (EXM) before gastrulation, in contrast to rodents where this tissue is formed only after gastrulation. Here, we discover that naive human pluripotent stem cells (hPSCs) are competent to differentiate into EXM cells (EXMCs). EXMCs are specified by inhibition of Nodal signaling and GSK3B, are maintained by mTOR and BMP4 signaling activity, and their transcriptome and epigenome closely resemble that of human and monkey embryo EXM. EXMCs are mesenchymal, can arise from an epiblast intermediate, and are capable of self-renewal. Thus, EXMCs arising via primate-specific specification between implantation and gastrulation can be modeled in vitro. We also find that most of the rare off-target cells within human blastoids formed by triple inhibition (Kagawa et al., 2021) correspond to EXMCs. Our study impacts our ability to model and study the molecular mechanisms of early human embryogenesis and related defects.

Keywords

extraembryonic mesoderm; human blastoids; human embryos; human naive pluripotent stem cells.

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