TY - JOUR
T1 - Molecular Criteria for Defining the Naive Human Pluripotent State
AU - Theunissen, Thorold W.
AU - Friedli, Marc
AU - He, Yupeng
AU - Planet, Evarist
AU - O'Neil, Ryan C.
AU - Markoulaki, Styliani
AU - Pontis, Julien
AU - Wang, Haoyi
AU - Iouranova, Alexandra
AU - Imbeault, Michaël
AU - Duc, Julien
AU - Cohen, Malkiel A.
AU - Wert, Katherine J.
AU - Castanon, Rosa
AU - Zhang, Zhuzhu
AU - Huang, Yanmei
AU - Nery, Joseph R.
AU - Drotar, Jesse
AU - Lungjangwa, Tenzin
AU - Trono, Didier
AU - Ecker, Joseph R.
AU - Jaenisch, Rudolf
N1 - Funding Information:
We thank Ruth Flannery for embryo processing, Patti Wisniewski and Colin Zollo for cell sorting, the University of Lausanne Genomic core facility for sequencing, and Dr. Jacob Hanna (Weizmann Institute) for sharing cells. This study was supported by grants from the Simons Foundation (SFLIFE #286977 to R.J.) and in part by the NIH (RO1-CA084198) to R.J., and from the Swiss National Science Foundation and the European Research Council (KRABnKAP, No. 268721) to D.T. The work in the J.R.E. laboratory was supported by the Howard Hughes Medical Institute and Gordon and Betty Moore Foundation (GBMF3034) and the Mary K. Chapman Foundation. J.R.E. is an Investigator of the Howard Hughes Medical Institute. T.W.T. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (098889/Z/12/Z), J.P. by a Foundation Bettencourt Award and by the Association pour la Recherche sur le Cancer (ARC), and M.I. by a postdoctoral training grant from the Fonds de la Recherche en Santé du Québec. R.J. is co-founder of Fate Therapeutics and an adviser to Stemgent.
Publisher Copyright:
© 2016 The Authors
PY - 2016/10/6
Y1 - 2016/10/6
N2 - Recent studies have aimed to convert cultured human pluripotent cells to a naive state, but it remains unclear to what extent the resulting cells recapitulate in vivo naive pluripotency. Here we propose a set of molecular criteria for evaluating the naive human pluripotent state by comparing it to the human embryo. We show that transcription of transposable elements provides a sensitive measure of the concordance between pluripotent stem cells and early human development. We also show that induction of the naive state is accompanied by genome-wide DNA hypomethylation, which is reversible except at imprinted genes, and that the X chromosome status resembles that of the human preimplantation embryo. However, we did not see efficient incorporation of naive human cells into mouse embryos. Overall, the different naive conditions we tested showed varied relationships to human embryonic states based on molecular criteria, providing a backdrop for future analysis of naive human pluripotency.
AB - Recent studies have aimed to convert cultured human pluripotent cells to a naive state, but it remains unclear to what extent the resulting cells recapitulate in vivo naive pluripotency. Here we propose a set of molecular criteria for evaluating the naive human pluripotent state by comparing it to the human embryo. We show that transcription of transposable elements provides a sensitive measure of the concordance between pluripotent stem cells and early human development. We also show that induction of the naive state is accompanied by genome-wide DNA hypomethylation, which is reversible except at imprinted genes, and that the X chromosome status resembles that of the human preimplantation embryo. However, we did not see efficient incorporation of naive human cells into mouse embryos. Overall, the different naive conditions we tested showed varied relationships to human embryonic states based on molecular criteria, providing a backdrop for future analysis of naive human pluripotency.
KW - DNA methylation
KW - X chromosome reactivation
KW - embryonic stem cells
KW - imprinting
KW - mouse-human chimeras
KW - pluripotency
KW - transposable elements
UR - http://www.scopus.com/inward/record.url?scp=84978887267&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2016.06.011
DO - 10.1016/j.stem.2016.06.011
M3 - Article
C2 - 27424783
AN - SCOPUS:84978887267
SN - 1934-5909
VL - 19
SP - 502
EP - 515
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 4
ER -