- Advanced synthetic embryos (sEmbryos) self-assembled from ESCs in an ex utero setup
- •Naive ESCs give rise to all embryonic and extraembryonic compartments in sEmbryos
- •Post-gastrulation stem cell derived sEmbryos develop organ-specific progenitors
- •Extraembryonic compartments adequately develop in post-gastrulation whole sEmbryos
SummaryIn vitro cultured stem cells with distinct developmental capacities can contribute to embryonic or extraembryonic tissues after microinjection into pre-implantation mammalian embryos. However, whether cultured stem cells can independently give rise to entire gastrulating embryo-like structures with embryonic and extraembryonic compartments remains unknown. Here, we adapt a recently established platform for prolonged ex utero growth of natural embryos to generate mouse post-gastrulation synthetic whole embryo models (sEmbryos), with both embryonic and extraembryonic compartments, starting solely from naive ESCs. This was achieved by co-aggregating non-transduced ESCs, with naive ESCs transiently expressing Cdx2 or Gata4 to promote their priming toward trophectoderm and primitive endoderm lineages, respectively. sEmbryos adequately accomplish gastrulation, advance through key developmental milestones, and develop organ progenitors within complex extraembryonic compartments similar to E8.5 stage mouse embryos. Our findings highlight the plastic potential of naive pluripotent cells to self-organize and functionally reconstitute and model the entire mammalian embryo beyond gastrulation.
Asynthetic embryo with cells capable of forming a brain and a beating heart was developed by researchers at the University of Cambridge using mouse stem cells. EuroNews described the effort as “yet another success in the unfolding race to develop embryos from human and mouse stem cells.”
The team, led by Professor Magdalena Zernicka-Goetz, developed the embryo model without using any eggs or sperm. The researchers used stem cells, specifically three types found in early mammalian development.
“By inducing the expression of a particular set of genes and establishing a unique environment for their interactions, the researchers were able to get the stem cells to ‘talk’ to each other,” explains a summary of the work.
“The stem cells self-organised into structures that progressed through the successive developmental stages until they had beating hearts and the foundations of the brain, as well as the yolk sac where the embryo develops and gets nutrients from in its first weeks.”
The synthetic embryo model developed by the Cambridge team is unique, as it reached a record level of development where the entire brain, including the anterior portion, began to develop.
The findings, which took researchers over a decade of work, could potentially be useful in understanding why some pregnancies fail along with developing synthetic organs for patients awaiting transplants.
The research also opens “new possibilities to study the mechanisms of neurodevelopment in an experimental model,” according to Zernicka-Goetz.
“In fact, we demonstrate the proof of this principle in the paper by knocking out a gene already known to be essential for formation of the neural tube, precursor of the nervous system, and for brain and eye development,” she continued.
“In the absence of this gene, the synthetic embryos show exactly the known defects in brain development as in an animal carrying this mutation. This means we can begin to apply this kind of approach to the many genes with unknown function in brain development.”
Damit sind in jedem Fall interessante Forschungsbereiche eröffnet und man könnte auch neue Aspekte der Fortpflanzung finden, wenn ich das richtig verstehe.
Aus der Studie:
Naive pluripotent stem cell growth conditions that utilize FGF/ mitogen-activated protein kinase (MEK) signaling inhibition cause loss of imprinting, which perturbs the developmental potential of such cells (Choi et al., 2017). This risk may possibly be mitigated in the future by using naive conditions while titrating down the concentration of inhibitors or alternative naive conditions (Bayerl et al., 2021; Shimizu et al., 2012). We note that eTSC lines show reduced yield in sEmbryo formation following prolonged passaging, consistent with reduction in Elf5+ cell fraction upon extended passaging (Figure S1E). The latter may be resolved by inducing naive ESCs toward becoming TE/TSCs that can be transiently induced during each aggregation experiment.
The reduced efficiency and heterogeneity observed during the formation of sEmbryos can be a complicating factor. Furthermore, day 8 sEmbryo formation efficiency is variable between ESC lines used, and some ESC lines tested could not generate sEmbryos beyond day 6 of the protocol. It is plausible that upon further experimentation, the efficiency and variability
in sEmbryo formation can be improved in the future. Furthermore, the ex utero system and conditions utilized herein have been shown to be able to support the growth of natural embryos up to E11 (Aguilera-Castrejon et al., 2021); however, sEmbryos described herein could only reach E8.5 so far. It gregation protocol or the ex utero growth platform can overcome this barrier. We cannot exclude that alternative ex utero culture platforms, aggregation strategies, or growth conditions might yield similar or enhanced results relative to the ones reported herein.
Finally, though most sEmbryos obtained show differences and abnormalities when stringently compared to natural embryos, the generation of integrated sEmbryos models that adequately complete gastrulation and initiate neurulation and organogenesis within the synthetic extraembryonic tissues surrounding them will likely be very useful as they can still be used to evaluate in vitro stem cell differentiation with greater complexity relative to any other currently available stem cellderived in vitro models.
Also, wenn ich es richtig verstehe, noch viel Arbeit. Gerade das Imprinting ist ja beim Versuch zu klonen ein großes Problem.