Conversion of mouse epiblast stem cells to an earlier pluripotency state by small molecules.
Epiblast stem cells (EpiSCs) are pluripotent cells derived from post-implantation late epiblasts in vitro. EpiSCs are incapable of contributing to chimerism, indicating that EpiSCs are less pluripotent and represent a later developmental pluripotency state compared with inner cell mass stage murine embryonic stem cells (mESCs). Using a chemical approach, we found that blockage of the TGFβ pathway or inhibition of histone demethylase LSD1 with small molecule inhibitors induced dramatic morphological changes in EpiSCs toward mESC phenotypes with simultaneous activation of inner cell mass-specific gene expression. However, full conversion of EpiSCs to the mESC-like state with chimerism competence could be readily generated only with the combination of LSD1, ALK5, MEK, FGFR, and GSK3 inhibitors. Our results demonstrate that appropriate synergy of epigenetic and signaling modulations could convert cells at the later developmental pluripotency state to the earlier mESC-like pluripotency state, providing new insights into pluripotency regulation.
Zhou
Hongyan
H
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Li
Wenlin
W
Zhu
Saiyong
S
Joo
Jin Young
JY
Do
Jeong Tae
JT
Xiong
Wen
W
Kim
Jeong Beom
JB
Zhang
Kang
K
Schöler
Hans R
HR
Ding
Sheng
S
D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects*; D002460:Cell Line; D046528:Chimerism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005855:Germ Layers; D056466:Histone Demethylases; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse