Statement Regarding Publication 2

  1. Irie N*, Weinberger L*, Tang W, Viukov S, Kobayashi T, Manor Y, Dietmann S, Hanna JH*# and Surani A#.

(*#Equal contribution and *#Equal co-corresponding senior author)

SOX17 is a Critical Specifier of Human Primordial Germ Cell Fate.

Cell (2015) 160(1-2):253-268. (92 citations)

{Featured on: Nature news, Channel 1 Israel news, LA Times, The Sunday Times, CBS news, MSNBC news, Yahoo news, Haaretz, Jerusalem Post, The Guardian}

  • Preview: Schubert C. The world of reproduction: Human primordial germ cells in a dish. Biology of Reproduction 91:114 (2015)
  • Preview: Deglincerti A & Brivanlu A. The generation of sex cells. Cell Research 25(3): 267-268 (2015).
  • Highlight: Baumann K. Human Primordial germ cells in a dish. Nature Reviews in Molecular and Cell Biology 16:68 (2015).
  • Selected for “Best of Cell 2015” top 10 published manuscripts list by Cell Editors ( ).

Summary and importance:

In vitro captured mouse pluripotent cells reside into two states: naïve (Embryonic stem cell (ESC)-like)) or primed (Epiblast stem cells (EpiSCs)-like) pluripotent states, each retaining molecular features of in vivo pre- and post-implantation epiblasts, respectively. The fact that conventional human ESCs and iPSCs rather resemble murine primed EpiSCs, have underscored a hypothesis (Hanna et al. Cell Stem Cell 2009, PNAS 2010, Cell 2010) of whether unique conditions can be developed to isolate previously unidentified alternative naïve-like pluripotent states from humans. My team was the first to devise naïve conditions, termed NHSM (commercialized by Stem Cell Technologies INC. – RseTTM), which entail complete ablation of MEK/ERK signalling and are compatible with expanding genetically unmodified human ESCs/iPSCs (Gafni et al. Nature 2013). These conditions contain MEKi/GSK3i/LIF (termed 2i/LIF) together with P38i, JNKi, PKCi, ROCKi, FGF2 and TGFβ1/ACTIVIN, and render human PSCs more similar, but not identical, to murine naïve PSCs. Based on molecules identified by our group to boost naïve pluripotency (e.g. PKCi, ROCKi, ACTIVIN), several papers have improved qualitative features of naivety and derived naïve human PSCs with distinct molecular flavors, all of which are of importance to be analyzed (Takashima et al. Cell 2014, Theunissen et al. Cell Stem Cell 2014).

Further, in Irie et al. Cell 2015 we showed that our human naïve PSCs have an enhanced potential to recapitulate a differentiation protocol, that until recently was successful only with mouse naïve PSCs, but not with human primed PSCs. Specifically, primordial germ cell-like cells (PGCLCs) can be induced in vitro from mouse naïve PSCs, after “priming” for two days in FGF2/ACTIVIN, followed by BMP4 stimulation. While reconstituting the PGC lineage with conventional primed human PSCs in vitro by applying the latter protocol has not been conductive, when using human naïve PSCs expanded in NHSM conditions, we were able to reconstitute human PGCLCs in vitro that are indistinguishable from human in vivo derived PGCs. Not stopping there, we uncovered species-specific transcriptional regulators of PGC induction (SOX17) differing between human and mice, and thus provided an important example for utilizing human stem cells for in vitro epistatic dissection of early human development. This authentic PGC differentiation platform is also being used for biochemical dissection of human in vitro reprogramming and toward advancing novel iPSC based infertility modeling and treatments.

Finally, this study underscores the direct influence of context dependent interpretation of signaling inputs during human naïve to primed pluripotency dynamic transitions, on establishing or resolving functional differentiation competence of iPSCs (in this case, specifically toward PGCs). In depth understanding of the molecular events dictating changes in functional competence will be key for framing the challenge of enabling researchers and clinicians to control stem cell behavior at will.