Format

Send to

Choose Destination
Nature. 2013 Dec 12;504(7479):282-6. doi: 10.1038/nature12745. Epub 2013 Oct 30.

Derivation of novel human ground state naive pluripotent stem cells.

Author information

1
1] The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel [2].
2
1] The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel [2] The Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [3] The Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel [4].
3
1] Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel [2] The Department of Cell and Developmental Biology, Sackler Medical School, Tel-Aviv University, Israel.
4
Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.
5
The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
6
1] The Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2] The Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
7
The Israel National Center for Personalized Medicine (INCPM), Weizmann Institute of Science, Rehovot 76100, Israel.
8
The Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.

Abstract

Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3β signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre-inactivation X chromosome state, and global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters. Upon withdrawal of 2i/LIF, naive mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include predominant use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalent domain acquisition on lineage regulatory genes. The feasibility of establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in mouse ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation of cross-species chimaeric mouse embryos that underwent organogenesis following microinjection of human naive iPS cells into mouse morulas. Collectively, our findings establish new avenues for regenerative medicine, patient-specific iPS cell disease modelling and the study of early human development in vitro and in vivo.

Comment in

PMID:
24172903
DOI:
10.1038/nature12745
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center