Pluripotency is highly dynamic in vivo and evolves at different stages of pre- and post-implantation development. However, the feature of self-renewal is a highly useful in vitro artificial phenotype that is endowed by culture conditions.
Different pluripotent cell types can be isolated in vitro from different sources and using different methods. The pluripotent state assumed by the cultivated cells is determined by their in vitro growth conditions, rather than by their cell of origin.
Naive and primed pluripotent states can be functionally classified on the basis of their ability or failure to maintain self-renewal of the pluripotent state upon inhibition of MEK signalling, respectively.
Naive and primed states of pluripotency represent a continuum of configurations rather than a fixed individual state. Within the naive and primed pluripotent states, different degrees of naivety or priming can be found, on the basis of various characteristics.
Human conventional pluripotent cells are primed; however, they are not identical to mouse primed cells and have certain naive-like properties. In vivo differences probably underlie the differences in growth requirements and characteristics of pluripotent cells isolated in vitro from mice and humans.
The use of human naive pluripotent growth conditions and cells might have marked effects on the quality of induced pluripotent stem cells and embryonic stem cells and their differentiation competence, consistency and robustness.
The molecular mechanisms and signalling pathways that regulate the in vitro preservation of distinct pluripotent stem cell configurations, and their induction in somatic cells by direct reprogramming, constitute a highly exciting area of research. In this Review, we integrate recent discoveries related to isolating unique naive and primed pluripotent stem cell states with altered functional and molecular characteristics, and from different species. We provide an overview of the pathways underlying pluripotent state transitions and interconversion in vitro and in vivo. We conclude by highlighting unresolved key questions, future directions and potential novel applications of such dynamic pluripotent cell states.
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J.H.H. is supported by a generous gift from Ilana and Pascal Mantoux, the New York Stem Cell Foundation (NYSCF), the Flight Attendant Medical Research Institute (FAMRI), the Kimmel Innovator Research Award, the European Research Council (ERC) Starting Grant (StG-2011-281906) and ERC Proof of Concept Grant (PoC-2015-692945), Moross Cancer Institute, Israel Science Foundation – Natural Science Foundation of China programme, Morasha Biomed programme, ICORE programme, the ICRF Foundation, MINERVA fund, Helen and Martin Kimmel Institute for Stem Cell research, the Benoziyo Endowment fund, David and Fela Shapell Family Foundation INCPM Fund for Preclinical Studies, and an HFSPO research grant. J.H.H. is a NYSCF Robertson Investigator. We thank W. Greenleaf and members of the Hanna laboratory for discussions. We apologize to those whose work could not be covered or directly cited owing to space limitations.
J.H.H. and N.N. have submitted patent applications and licensed commercialization of some of the pluripotency regulation pathways and methods discussed in this Review.
- Primordial germ cells
(PGCs). Embryonic progenitor cells that give rise to germ cells in the gonads (sperm and oocytes).
- Embryonic stem cells
(ES cells). In vitro-expanded pluripotent cells that originate from the inner cell mass.
- Inner cell mass
(ICM). The mass of cells inside the pre-implantation blastocyst that will subsequently give rise to the definitive structures of the fetus.
- Epiblast stem cells
(EpiSCs). In vitro-expanded pluripotent cells that originate from the post-implantation epiblast.
- Embryonic germ cells
In vitro-expanded pluripotent cells that are derived from embryonic primordial germ cells (PGCs).
- Germ stem cells
(GSCs). In vitro-expanded pluripotent stem cells that originate from neonatal or adult testis-derived spermatogonial stem cells.
- Nuclear transfer
The cloning of a somatic cell-derived nucleus and its introduction into an anucleated host oocyte.
- Induced pluripotent stem cells
(iPSCs). In vitro-generated pluripotent cells derived by the ectopic expression of defined exogenous factors in somatic cells.
- X inactivation
Dosage compensation of the X chromosome in females, whereby one of the X chromosomes is epigenetically silenced.
- Naive pluripotency
A pluripotent state that resembles the pre-implantation embryonic configuration(s).
- Primed pluripotency
A pluripotent state that resembles the post-implantation embryonic configuration(s).
- 3i conditions
Defined naive pluripotency growth conditions combining three inhibitors (i) for MEK, fibroblast growth factor (FGF) and glycogen synthase kinase 3 (GSK3) signalling.
- Ground state pluripotency
Originally described as a state of pluripotency that is independent of exogenous activator signalling input or stimulation.
- 2i/LIF conditions
Defined naive pluripotency growth conditions containing two inhibitors (i) for MEK and GSK3, together with LIF cytokine.
- Alternative 2i conditions
Defined naive pluripotency growth conditions containing two inhibitors (i) for the glycogen synthase kinase 3 (GSK3) and SRC pathways.
- LIF/MEKi/aPKCi conditions
Defined naive pluripotency growth conditions containing two inhibitors (i) for MEK and atypical protein kinase C (aPKC) signalling, together with the leukaemia inhibitory factor (LIF) cytokine.
- FGF2/Activin A conditions
Defined primed pluripotency growth conditions for mouse epiblast stem cells, composed of recombinant fibroblast growth factor 2 (FGF2) and Activin A cytokines.
- Seed enhancers
A subgroup of enhancers that are dormant in naive cells but become more active in primed pluripotent and somatic cells.
- GSK3i/IWR1 conditions
Defined primed pluripotency growth conditions for mouse epiblast stem cells, containing a glycogen synthase kinase 3 (GSK3) pathway inhibitor and the small-molecule tankyrase inhibitor, IWR1.
- FGF2/IWR1 conditions
Defined primed pluripotency growth conditions for mouse epiblast stem cells, containing recombinant fibroblast growth factor 2 (FGF2) and the small-molecule tankyrase inhibitor, IWR1.
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Weinberger, L., Ayyash, M., Novershtern, N. et al. Dynamic stem cell states: naive to primed pluripotency in rodents and humans. Nat Rev Mol Cell Biol 17, 155–169 (2016). https://doi.org/10.1038/nrm.2015.28
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