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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Hanna, J. H., Saha, K. & Jaenisch, R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508–525 (2010).
Nichols, J. & Smith, A. Pluripotency in the embryo and in culture. Cold Spring Harb. Perspect. Biol. 4, a008128 (2012).
Hackett, J. A. & Surani, M. A. Regulatory principles of pluripotency: from the ground state up. Cell Stem Cell 15, 416–430 (2014).
Manor, Y. S., Massarwa, R. & Hanna, J. H. Establishing the human naive pluripotent state. Curr. Opin. Genet. Dev. 34, 35–45 (2015).
Inoue, H., Nagata, N., Kurokawa, H. & Yamanaka, S. iPS cells: a game changer for future medicine. EMBO J. 33, 409–417 (2014).
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998). The first study to derive primed ES cells from human blastocysts.
Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).
Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).
Tesar, P. J. et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199 (2007).
Brons, I. G. et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191–195 (2007). References 9 and 10 describe the derivation of primed EpiSC lines from rodent post-implantation epiblasts.
Leitch, H. G. et al. Embryonic germ cells from mice and rats exhibit properties consistent with a generic pluripotent ground state. Development 137, 2279–2287 (2010).
Matsui, Y., Zsebo, K. & Hogan, B. L. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70, 841–847 (1992). The first study to describe the generation of pluripotent ES cell-like cells from mouse embryonic PGCs.
Kanatsu-Shinohara, M. et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell 119, 1001–1012 (2004). The first study to describe the generation of pluripotent ES cell-like cells from mouse spermatogonial stem cells.
Tanaka, T., Kanatsu-Shinohara, M., Hirose, M., Ogura, A. & Shinohara, T. Pluripotent cell derivation from male germline cells by suppression of Dmrt1 and Trp53. J. Reprod. Dev. 61, 473–484 (2015).
Ko, K. et al. Induction of pluripotency in adult unipotent germline stem cells. Cell Stem Cell 5, 87–96 (2009).
Ko, K. et al. Human adult germline stem cells in question. Nature 465, E1; discussion E3 (2010).
Shamblott, M. J. et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc. Natl Acad. Sci. USA 95, 13726–13731 (1998).
Yamada, M. et al. Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. Nature 510, 533–536 (2014).
Tachibana, M. et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 1228–1238 (2013). The first study to generate validated human NT-ES cells from somatic fibroblasts.
Wakayama, T. et al. Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292, 740–743 (2001). This study shows the feasibility of somatic cell nuclear transfer in mice.
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). This is the first study to show direct in vitro reprogramming of somatic cells into iPSCs using defined transcription factors.
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Deuse, T. et al. SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts. Cell Stem Cell 16, 33–38 (2015).
Ma, H. et al. Metabolic rescue in pluripotent cells from patients with mtDNA disease. Nature 524, 234–238 (2015).
Tachibana, M. et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461, 367–372 (2009).
Paull, D. et al. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature 493, 632–637 (2013).
Hanna, J. et al. Metastable pluripotent states in NOD-mouse-derived ESCs. Cell Stem Cell 4, 513–524 (2009). The first study to define distinct requirements in different mouse strains for in vitro and ex vivo conversions between naive and primed pluripotent cells.
Nichols, J. & Smith, A. Naive and primed pluripotent states. Cell Stem Cell 4, 487–492 (2009).
Han, D. W. et al. Direct reprogramming of fibroblasts into epiblast stem cells. Nat. Cell Biol. 13, 66–71 (2011).
Najm, F. J. et al. Isolation of epiblast stem cells from preimplantation mouse embryos. Cell Stem Cell 8, 318–325 (2011).
Martin, G. R. & Evans, M. J. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc. Natl Acad. Sci. USA 72, 1441–1445 (1975).
Smith, A. G. et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336, 688–690 (1988).
Williams, R. L. et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336, 684–687 (1988).
Orkin, S. H. & Hochedlinger, K. Chromatin connections to pluripotency and cellular reprogramming. Cell 145, 835–850 (2011).
Ying, Q. L., Nichols, J., Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self renewal in collaboration with STAT3. Cell 115, 281–292 (2003).
Burdon, T., Stracey, C., Chambers, I., Nichols, J. & Smith, A. Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev. Biol. 210, 30–43 (1999).
Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008). A study describing defined 3i naive conditions capable of generating LIF- and STAT3-independent mouse ES cells.
Buehr, M. et al. Capture of authentic embryonic stem cells from rat blastocysts. Cell 135, 1287–1298 (2008).
Nichols, J. et al. Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat. Med. 15, 814–818 (2009).
Chen, H. et al. Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 112, E5936–E5943 (2015).
Shimizu, T. et al. Dual inhibition of Src and GSK3 maintains mouse embryonic stem cells, whose differentiation is mechanically regulated by Src signaling. Stem Cells 30, 1394–1404 (2012).
Dutta, D. et al. Self-renewal versus lineage commitment of embryonic stem cells: protein kinase C signaling shifts the balance. Stem Cells 29, 618–628 (2011). The first study using aPKCi to boost the generation of naive murine iPSCs and ES cells.
Kolodziejczyk, A. A. et al. Single cell RNA-sequencing of pluripotent states unlocks modular transcriptional variation. Cell Stem Cell 17, 471–485 (2015).
Chen, Y., Blair, K. & Smith, A. Robust self-renewal of rat embryonic stem cells requires fine-tuning of glycogen synthase kinase-3 inhibition. Stem Cell Rep. 1, 209–217 (2013).
Meek, S. et al. Tuning of β-catenin activity is required to stabilize self-renewal of rat embryonic stem cells. Stem Cells 31, 2104–2115 (2013).
Rajendran, G. et al. Inhibition of protein kinase C signaling maintains rat embryonic stem cell pluripotency. J. Biol. Chem. 288, 24351–24362 (2013).
Li, X. et al. Calcineurin-NFAT signaling critically regulates early lineage specification in mouse embryonic stem cells and embryos. Cell Stem Cell 8, 46–58 (2011). The first study to show that Src inhibition promotes murine naive pluripotency.
Nishioka, N. et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev. Cell 16, 398–410 (2009). This study identifies the role of the HIPPO signalling pathway in epiblast versus trophoblast specification in pre-implantation mouse embryos.
Azzolin, L. et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).
Lian, I. et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 24, 1106–1118 (2010).
Wray, J. et al. Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nat. Cell Biol. 13, 838–845 (2011).
Faunes, F. et al. A membrane-associated β-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. Development 140, 1171–1183 (2013).
Morgani, S. M. & Brickman, J. M. LIF supports primitive endoderm expansion during pre-implantation development. Development 142, 3488–3499 (2015).
Silva, J. et al. Nanog is the gateway to the pluripotent ground state. Cell 138, 722–737 (2009).
Maza, I. et al. Transient acquisition of pluripotency during somatic cell transdifferentiation with iPSC reprogramming factors. Nat. Biotechnol. 33, 769–774 (2015).
Carter, A. C., Davis-Dusenbery, B. N., Koszka, K., Ichida, J. K. & Eggan, K. Nanog-independent reprogramming to iPSCs with canonical factors. Stem Cell Rep. 2, 119–126 (2014).
Schwartz, B. A. et al. Nanog is dispensable for the generation of induced pluripotent stem cells. Curr. Biol. 24, 347–350 (2014).
Festuccia, N. et al. Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. Cell Stem Cell 11, 477–490 (2012).
Yeo, J. C. et al. Klf2 is an essential factor that sustains ground state pluripotency. Cell Stem Cell 14, 864–872 (2014).
Reynolds, N. et al. NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment. Cell Stem Cell 10, 583–594 (2012). This study establishes MBD3–NuRD as a repressor of naive pluripotency-promoting genes in mouse ES cells.
Rais, Y. et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502, 65–70 (2013).
Loh, K. M. & Lim, B. A precarious balance: pluripotency factors as lineage specifiers. Cell Stem Cell 8, 363–369 (2011).
Geula, S. et al. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015). The first study to show an opposing dependence on epigenetic repressors between mouse naive and primed PSCs.
Huang, Y. et al. In vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation. Cell Rep. 2, 1571–1578 (2012).
Buecker, C. et al. Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell Stem Cell 14, 838–853 (2014).
Marks, H. et al. The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149, 590–604 (2012).
Gafni, O. et al. Derivation of novel human ground state naive pluripotent stem cells. Nature 504, 282–286 (2013). The first study to generate genetically unmodified and indefinitely stable human MEK-independent naive PSCs, which were also capable of generating advanced mouse–human chimeric embryos.
Factor, D. C. et al. Epigenomic comparison reveals activation of “seed” enhancers during transition from naive to primed pluripotency. Cell Stem Cell 14, 854–863 (2014).
Kumar, R. M. et al. Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature 516, 56–61 (2014).
Kim, H. et al. Modulation of β-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. Nat. Commun. 4, 2403 (2013).
Kojima, Y. et al. The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14, 107–120 (2014).
Wu, J. et al. An alternative pluripotent state confers interspecies chimaeric competency. Nature 521, 316–321 (2015). References 74 and 75 are the first two studies describing region-specific features of mouse EpiSCs expanded in vitro.
Han, D. W. et al. Epiblast stem cell subpopulations represent mouse embryos of distinct pregastrulation stages. Cell 143, 617–627 (2010).
Hayashi, K., Ohta, H., Kurimoto, K., Aramaki, S. & Saitou, M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146, 519–532 (2011).
Guo, G. et al. Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063–1069 (2009). Together with reference 30, one of two studies that are the first to show conversion between murine naive and primed pluripotent cells.
Bao, S. et al. Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292–1295 (2009).
Gillich, A. et al. Epiblast stem cell-based system reveals reprogramming synergy of germline factors. Cell Stem Cell 10, 425–439 (2012).
Greber, B. et al. Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells. Cell Stem Cell 6, 215–226 (2010).
Leitch, H. G. et al. Naive pluripotency is associated with global DNA hypomethylation. Nat. Struct. Mol. Biol. 20, 311–316 (2013).
Ficz, G. et al. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13, 351–359 (2013).
Hackett, J. A. et al. Synergistic mechanisms of DNA demethylation during transition to ground-state pluripotency. Stem Cell Rep. 1, 518–531 (2013).
Galonska, C., Ziller, M. J., Karnik, R. & Meissner, A. Ground state conditions induce rapid reorganization of core pluripotency factor binding before global epigenetic reprogramming. Cell Stem Cell 17, 462–470 (2015).
Liao, J. et al. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat. Genet. 47, 469–478 (2015).
Tee, W. W., Shen, S. S., Oksuz, O., Narendra, V. & Reinberg, D. Erk1/2 activity promotes chromatin features and RNAPII phosphorylation at developmental promoters in mouse ESCs. Cell 156, 678–690 (2014).
Bertero, A. et al. Activin/Nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. Genes Dev. 29, 702–717 (2015).
Smith, Z. D. et al. DNA methylation dynamics of the human preimplantation embryo. Nature 511, 611–615 (2014).
Mekhoubad, S. et al. Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell 10, 595–609 (2012).
Chia, N. Y. et al. A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature 468, 316–320 (2010).
Shipony, Z. et al. Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells. Nature 513, 115–119 (2014).
Betschinger, J. et al. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell 153, 335–347 (2013).
Hanna, J. et al. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc. Natl Acad. Sci. USA 107, 9222–9227 (2010). This study provides the first evidence for alternative transgene-dependent human PSCs that can be expanded in conditions containing 2i and LIF.
Theunissen, T. W. et al. Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 15, 471–487 (2014).
Takashima, Y. et al. Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158, 1254–1269 (2014).
Blakeley, P. et al. Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development 142, 3151–3165 (2015).
Gkountela, S. et al. DNA demethylation dynamics in the human prenatal germline. Cell 161, 1425–1436 (2015).
Shakiba, N. et al. CD24 tracks divergent pluripotent states in mouse and human cells. Nat. Commun. 6, 7329 (2015).
Barakat, T. S. et al. Stable X chromosome reactivation in female human induced pluripotent stem cells. Stem Cell Rep. 4, 199–208 (2015).
Chan, Y. S. et al. Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. Cell Stem Cell 13, 663–675 (2013).
Duggal, G. et al. Alternative routes to induce naive pluripotency in human embryonic stem cells. Stem Cells 33, 2686–2698 (2015).
Chen, H. et al. Reinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency. Nat. Commun. 6, 7095 (2015).
Ohgushi, M., Minaguchi, M. & Sasai, Y. Rho-signaling-directed YAP/TAZ activity underlies the long-term survival and expansion of human embryonic stem cells. Cell Stem Cell 17, 448–461 (2015). A study connecting RHO and HIPPO signalling pathways in the maintenance of human primed pluripotency.
Kameda, T. & Thomson, J. A. Human ERas gene has an upstream premature polyadenylation signal that results in a truncated, noncoding transcript. Stem Cells 23, 1535–1540 (2005).
Boroviak, T. et al. Lineage-specific profiling delineates the emergence and progression of naive pluripotency in mammalian embryogenesis. Dev. Cell 35, 366–382 (2015).
Buecker, C. & Wysocka, J. Enhancers as information integration hubs in development: lessons from genomics. Trends Genet. 28, 276–284 (2012).
Karwacki-Neisius, V. et al. Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog. Cell Stem Cell 12, 531–545 (2013).
Boroviak, T., Loos, R., Bertone, P., Smith, A. & Nichols, J. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat. Cell Biol. 16, 516–528 (2014).
Osafune, K. et al. Marked differences in differentiation propensity among human embryonic stem cell lines. Nat. Biotechnol. 26, 313–315 (2008).
Irie, N. et al. SOX17 is a critical specifier of human primordial germ cell fate. Cell 160, 253–268 (2015). The first study to generate human PGC-like cells in vitro and demonstrate altered function of human MEK-independent naive PSCs.
Bock, C. et al. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439–452 (2011).
Kobayashi, T. et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142, 787–799 (2010). The first study to generate cross-species chimerism between mice and rats by microinjecting naive PSCs from one species into host blastocysts from the other.
Chen, Y. et al. Generation of cynomolgus monkey chimeric fetuses using embryonic stem cells. Cell Stem Cell 17, 116–124 (2015). A study demonstrating the first chimeric monkey fetuses to be generated, using naive monkey ES cells established in NHSM conditions supplemented with vitamin C.
Fang, R. et al. Generation of naive induced pluripotent stem cells from rhesus monkey fibroblasts. Cell Stem Cell 15, 488–496 (2014).
Bock, A. S., Leigh, N. D. & Bryda, E. C. Effect of Gsk3 inhibitor CHIR99021 on aneuploidy levels in rat embryonic stem cells. In Vitro Cell Dev. Biol. Anim. 50, 572–579 (2014).
Qin, H. et al. Systematic identification of barriers to human iPSC generation. Cell 158, 449–461 (2014).
Kim, K. et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat. Biotechnol. 29, 1117–1119 (2011).
Choi, J. et al. A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. Nat. Biotechnol. 33, 1173–1181 (2015).
Ma, H. et al. Abnormalities in human pluripotent cells due to reprogramming mechanisms. Nature 511, 177–183 (2014).
Pastor, W. A. et al. Naive human pluripotent cells feature a methylation landscape devoid of blastocyst or germline memory. Cell Stem Cell http://dx.doi.org/10.1016/j.stem.2016.01.019 (2016).
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.
Supplementary information S1 (figure)
Naive and primed pluripotent cell properties in isolated pluripotent stem cells (PSCs) from different species. (PDF 184 kb)
- 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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