Modeling human extraembryonic mesoderm cells using naive pluripotent stem cells
Thi Xuan Ai Pham, Amitesh Panda, Harunobu Kagawa, San Kit To, Cankat Ertekin, Grigorios Georgolopoulos, Sam Samuel Franciscus Allegonda van Knippenberg, Ryan Allsop, Alexandre Bruneau, Jonathan Sai‐Hong Chui, Lotte Vanheer, Adrian Janiszewski, Joel Chappell, Michael Oberhuemer, Raissa Songwa Tchinda, Irene Talón, Sherif Khodeer, Janet Rossant, Frederic Lluı́s, Laurent David, Nicolas Rivron, Bradley P. Balaton, Vincent Pasque
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.