Epiblast-like stem cells established by Wnt/β-catenin signaling manifest distinct features of formative pluripotency and germline competence
Qing Luo,
Han-pin Pui,
Jiayu Chen,
Leqian Yu,
Paulo R. Jannig,
Yu Pei,
Linxuan Zhao,
Xingqi Chen,
Sophie Petropoulos,
Jorge L. Ruas,
Jun Wu,
Qiaolin Deng
Affiliations
Qing Luo
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
Han-pin Pui
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, 171 77 Stockholm, Sweden; Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, 141 52 Huddinge, Sweden
Jiayu Chen
Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 20092, China; Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 20092, China
Leqian Yu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Paulo R. Jannig
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
Yu Pei
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, 171 77 Stockholm, Sweden
Linxuan Zhao
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Xingqi Chen
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Sophie Petropoulos
Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, 141 52 Huddinge, Sweden; Department of Medicine, Centre de recherche du CHUM, University of Montreal, Montreal, QC H2X 0A9, Canada
Jorge L. Ruas
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
Jun Wu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Qiaolin Deng
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, 171 77 Stockholm, Sweden; Corresponding author
Summary: Different formative pluripotent stem cells harboring similar functional properties have been recently established to be lineage neutral and germline competent yet have distinct molecular identities. Here, we show that WNT/β-catenin signaling activation sustains transient mouse epiblast-like cells as epiblast-like stem cells (EpiLSCs). EpiLSCs display metastable formative pluripotency with bivalent cellular energy metabolism and unique transcriptomic features and chromatin accessibility. We develop single-cell stage label transfer (scSTALT) to study the formative pluripotency continuum and reveal that EpiLSCs recapitulate a unique developmental period in vivo, filling the gap of the formative pluripotency continuum between other published formative stem cells. WNT/β-catenin signaling activation counteracts differentiation effects of activin A and bFGF by preventing complete dissolution of naive pluripotency regulatory network. Moreover, EpiLSCs have direct competence toward germline specification, which is further matured by an FGF receptor inhibitor. Our EpiLSCs can serve as an in vitro model for mimicking and studying early post-implantation development and pluripotency transition.
