1. Activin A and BMP4 Signaling Expands Potency of Mouse Embryonic Stem Cells in Serum-Free Media
- Author
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M. Azim Surani, Mengyi Wei, Junpeng Gao, Fuchou Tang, Zhiqing Yang, Siqin Bao, Lin Li, Baojiang Wu, Xihe Li, Kexin Li, Changshan Wang, Baojing Zhang, Yanglin Chen, Bojiang Li, Shudong Li, Surani, Azim [0000-0002-8640-4318], Apollo - University of Cambridge Repository, and Bao, Siqin [0000-0002-9582-3194]
- Subjects
0301 basic medicine ,Bone Morphogenetic Protein 4 ,Biochemistry ,chemically defined ,Culture Media, Serum-Free ,Germline ,Epigenesis, Genetic ,Mice ,0302 clinical medicine ,implantation ,Cell Self Renewal ,lcsh:QH301-705.5 ,reproductive and urinary physiology ,lcsh:R5-920 ,Tetraploid complementation assay ,Mouse Embryonic Stem Cells ,embryonic stem cells ,genomic imprinting ,Activins ,Up-Regulation ,3. Good health ,Cell biology ,hypermethylation ,medicine.anatomical_structure ,embryonic structures ,DNA methylation ,biological phenomena, cell phenomena, and immunity ,Stem cell ,lcsh:Medicine (General) ,Signal Transduction ,Pluripotent Stem Cells ,Biology ,Article ,Genomic Instability ,03 medical and health sciences ,Genetics ,medicine ,Animals ,Blastocyst ,development ,Protein Kinase Inhibitors ,mouse ,Mitogen-Activated Protein Kinase Kinases ,epigenetics ,blastocyst ,urogenital system ,Cell Biology ,DNA Methylation ,pluripotency ,Embryonic stem cell ,Chemically defined medium ,030104 developmental biology ,lcsh:Biology (General) ,Leukemia inhibitory factor ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Summary Inhibitors of Mek1/2 and Gsk3β, known as 2i, and, together with leukemia inhibitory factor, enhance the derivation of embryonic stem cells (ESCs) and promote ground-state pluripotency (2i/L-ESCs). However, recent reports show that prolonged Mek1/2 suppression impairs developmental potential of ESCs, and is rescued by serum (S/L-ESCs). Here, we show that culturing ESCs in Activin A and BMP4, and in the absence of MEK1/2 inhibitor (ABC/L medium), establishes advanced stem cells derived from ESCs (esASCs). We demonstrate that esASCs contributed to germline lineages, full-term chimeras and generated esASC-derived mice by tetraploid complementation. We show that, in contrast to 2i/L-ESCs, esASCs display distinct molecular signatures and a stable hypermethylated epigenome, which is reversible and similar to serum-cultured ESCs. Importantly, we also derived novel ASCs (blASCs) from blastocysts in ABC/L medium. Our results provide insights into the derivation of novel ESCs with DNA hypermethylation from blastocysts in chemically defined medium., Graphical Abstract, Highlights • Activin A and BMP4 expand potency of mouse ESCs • ASCs are hypermethylated and with stable genomic imprints • ASCs developmentally closed to E4.5–E6.5 in vivo epiblast • Hypermethylated ASCs directly derived from blastocyst by ABC/L medium, In this article, Bao and colleagues show that ASCs cultured in Activin A and BMP4, and in the absence of MEK1/2 inhibitor, possess reversible epigenetic changes that extend their developmental potency, distinct transcriptome pattern, and a stable hypermethylated epigenome. Importantly, they also derived novel hypermethylated ASCs from blastocysts in ABC/L medium.
- Published
- 2020