naive-primed review

Understanding Naïve and Primed Pluripotent States

Being able to generate all cell types, mouse embryonic stem cells are a most valuable tool for research. They can be found in the developing mouse embryo in two distinct states: naïve - in the blastocyst, and primed - in the post-implantation epiblast. These two states are distinct in various aspects, most notable, only naïve cells can contribute efficiently to chimera. Naïve and primed cells can be sustained in-vitro, and are dependent on distinct signaling. In human, naïve stem cells were out of reach for a long time. We investigate the regulation of naïve and primed pluripotent stem cell in mouse and human. Specifically, we were able to maintain human stem cells in a "naive" state, with distinct molecular and functional properties, including enhanced ability to contribute to cross-species mouse chimeric embryos (Gafni et al, 2013). In addition, we found that mRNA methylation has a critical role in facilitating degradation of pluripotent genes, an essential step during the switch from naïve to primed states, both in-vitro and in-vivo (Geula et al, 2014). Our current studies involve elucidating molecular regulation of these states across different species, and define how their molecular architecture dictates their functional competence.
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Ex Utero Embryogenesis: From Stem Cells to Organs

Studying mammalian development is crucial for understanding the basis of developmental defects and for devising protocols for inducedpluripotent stem cell (iPSC) in vitro differentiation which can be used for cell transplantation. The inaccessibility of the advanced natural mammalian embryo due to its intimate association with the maternal uterus, that constitutes a “black box”, has been a major constraint for investigating mammalian development at high resolution from all mammalian species. Our group has recently established a robust electronically controlled ex utero whole embryo culture platforms that allow capturing normal mouse embryogenesis from pre-gastrulation (E5.5) until advanced organogenesis (E11) ex utero (Aguilera-Castrejon et al. Nature 2021). Our work established for the first time in a mammalian species, i.e. in mice, that the processes of gastrulation and organogenesis can be jointly and continuously recapitulated adequately in the petri dish. Importantly, these systems allow introducing genetic perturbations at early stages of development ex utero and following their effects after culture until advanced stages, rendering them highly relevant for mouse embryology and stem cell research. We view the ability to continuously capture and perturb mouse gastrulation and organogenesis ex utero as a newly revived area of research that necessitates further extensive technology development in order to harness the full potential of this biotechnology and extending it to other mammalian model organisms that better resemble human embryo development (e.g. Rabbits and monkeys).
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Stem-Cell-Derived (Synthetic) Embryo Models (SEMs)

The novel extended ex utero culture systems to grow mouse natural embryos through gastrulation and organogenesis that our group has recently developed, represent a long-awaited gold standard reference that will allow evaluating and improving the developmental potential of stem-cell-derived (synthetic) embryoid models generated by co-aggregating in vitro expanded stem cell lines. This line of research is conducted by utilizing in house developed electronic devices, advanced tissue culture capabilities, stem cell based cellular models combined with cutting-edge genomic editing, transgenics, advanced microscopy, optogenetics and single cell biology. Recently, we have shown that by starting solely with mouse naïve ESCs, we can unleash their ability to self-organize into embryoid models (termed SEMs or sEmbryos) that reach day 8.5 after completing gastrulation and initiating organogenesis. (Tarazi et al. Cell 2022). This line of work may open a new path for developmental biology research and might establish universal platforms for generating early progenitor populations from iPSCs from a variety of species, via correctly inducing complex self-organization of stem cells in these unique artificial ex utero settings, that can be then used in stem cell differentiation research and bioengineering.
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Deciphering Cellular Reprogramming

Following a breakthrough that was made in 2006 (by Takahashi & Yamanaka), today we can reverse cellular differentiation, and generate induced pluripotent stem cells from somatic cells by epigenetic “reprogramming”. We investigate what are the dramatic molecular changes happening in the cell during reprogramming and how they are connected to similar in-vivo processes. We pointed out two chromatin regulators that play a role in this process, one is essential for reprogramming (Utx, Mansour et al 2012), and the other (Mbd3, Rais et al 2013) is an obstacle, which upon its near-removal the reprogramming becomes dramatically faster and synchronized.
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Human-Mouse Cross-Species Chimerism

Human stem cells that are sustained in naïve culture conditions, can be injected to mouse blastocyst and contribute to cross-species chimera (Gafni et al, 2013). We investigate these chimeric mice, which are valuable tool for human disease modeling in a whole-organism context.
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