Human naive epiblast cells possess unrestricted lineage potential.

Integrated pseudotime analysis of human pre-implantation embryo single-cell transcriptomes reveals the dynamics of lineage specification.

Tese de doutoramento em Biologia (Biologia Molecular) apresentada a Fac. de Ciencias e Tecnologia da Univ. de Coimbra

Regulation of apoptosis and differentiation by P53 in human embryonic stem cells

SUMMARY Classical mouse embryology has established a paradigm of early development driven by sequential lineage bifurcations. Accordingly, mouse embryonic stem cells derived from early epiblast have lost the potency to produce extraembryonic trophectoderm. We show in contrast that human naive epiblast cells readily make trophectoderm. Inhibition of ERK signalling, instrumental in naive stem cell propagation, unexpectedly potentiates trophectoderm formation, an effect enhanced by Nodal inhibition. Transcriptome analyses authenticate conversion into trophectoderm with subsequent production of syncitiotrophoblast, cytotrophoblast and trophoblast stem cells. Genetic perturbations indicate that NANOG suppresses and TFAP2C enables trophectoderm induction. Consistent with post-implantation progression, trophectoderm potential is extinguished in conventional human pluripotent stem cells, which instead make amnion. Finally, human embryo epiblasts from late blastocysts efficiently generate trophectoderm and differentiated trophoblast. Thus, pluripotent cells in the human embryo retain extraembryonic lineage plasticity and regenerative potential until implantation. Harnessing this unanticipated regulative capacity may be beneficial for assisted reproduction technology.

/pdf/human-naive-epiblast-cells-possess-unrestricted-lineage-127mkkhd9f.pdf

Human Naïve Epiblast Cells Possess Unrestricted Lineage Potential

Naive human pluripotent stem cells have the remarkable ability to self-organize into blastocyst-like structures ("blastoids") that model lineage segregation in the pre-implantation embryo. However, the extent to which blastoids can recapitulate the defining features of human post-implantation development remains unexplored. Here, we report that blastoids cultured on thick three-dimensional (3D) extracellular matrices capture hallmarks of early post-implantation development, including epiblast lumenogenesis, rapid expansion and diversification of trophoblast lineages, and robust invasion of extravillous trophoblast cells by day 14. Extended blastoid culture results in the localized activation of primitive streak marker TBXT and the emergence of embryonic germ layers by day 21. We also show that the modulation of WNT signaling alters the balance between epiblast and trophoblast fates in post-implantation blastoids. This work demonstrates that 3D-cultured blastoids offer a continuous and integrated in vitro model system of human embryonic and extraembryonic development from pre-implantation to early gastrulation stages. 

3D-cultured blastoids model human embryogenesis from pre-implantation to early gastrulation stages.

Comprehensive understanding of lineage differentiation and apoptosis processes is important to increase our knowledge of human preimplantation development in vitro. We know that BMP signaling is important for different processes during mammalian development. In mouse preimplantation embryos, BMP signaling has been shown to play a role in the differentiation into extra-embryonic trophectoderm (TE) and primitive endoderm (PE). In this study, we aimed to investigate the effect of bone morphogenetic protein 4 (BMP4) supplementation on human preimplantation embryos cultured in vitro. The BMP4 treatment impaired human blastocyst formation. No differences in the expression of the early lineage markers NANOG, CDX2, GATA3, and GATA6 were found between BMP4-treated embryos and controls. Instead, BMP4 supplementation triggered apoptosis in the human blastocyst. We focused on P53, which is known to play a major role in the apoptosis. In BMP4-treated embryos, the P53 responsive gene expression was not altered; however, the P53 deacetylase SIRT1 was downregulated and acetylated P53 was increased in mitochondria. Altogether, our findings suggest that BMP4 plays a role in the apoptosis during human preimplantation development.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mrd.23081

BMP4 plays a role in apoptosis during human preimplantation development.

Considerable evidence suggests that circadian rhythmicity is progressively disrupted in senescence. Among clock genes, Period3 (PER3) has been associated with circadian phenotypes, homeostatic regulation of sleep, and cognitive performance in young adults. However, the effects of PER3 genotype on aging-related changes in both cognitive function and cortical integrity remain largely unknown. To shed light into this issue, we have investigated differences in cognitive performance, patterns of cortical thickness, and cortical glucose consumption in normal elderly subjects homozygous carriers of the short (PER34/4, n = 32) and long repeat alleles (PER35/5, n = 32). Relationships between cognitive performance and cortical thickness/metabolism were further explored for each PER3 genotype. We found that PER35/5 carriers had poorer cognitive performance (attention, executive function, semantic memory, and verbal fluency) and lower cortical integrity (structural and functional) than PER34/4. PER35/5 further showed thinning of temporo–parietal areas, and reductions of glucose consumption in fronto–temporo–parietal regions bilaterally. Moreover, PER35/5 subjects exhibited significant correlations between decreased glucose metabolism in fronto–parietal regions and poorer cognitive flexibility, though only correlations with lower glucose consumption of the supramarginal gyrus distinguished PER35/5 from PER34/4 groups. Overall, these findings enhance our understanding on the gene–brain interaction in aging, and may have further implications for the detection of subclinical cognitive decline associated with PER3 genotypes in late life.

Effects of PER3 clock gene polymorphisms on aging-related changes of the cerebral cortex.

We know that polarity and YAP1 play a key role in trophectoderm initiation in compacted human embryos, however we know little about the TEAD family of transcription factors that become activated by YAP1 and especially if they play a role during epiblast and primitive endoderm formation. Here we show that compaction occurs heterogeneously between the 8- and 16-cell stages. While 8-cell stage blastomeres are not yet polarized, polarized outer cells and non-polarized inner cells arise in compacted 16-cell stage embryos. While trophectoderm specifiers TEAD1, YAP1 and GATA3 mostly co-localise in the nuclei of polarized outer/trophectoderm cells, they are also found in some cells of compacting embryos before polarity is established indicating that differentiation into trophectoderm cells can be initiated independently of polarity. In the inner cell mass, TEAD1 and YAP1 also distinguish GATA4 positive cells in a salt-and-pepper distribution and in the sorted primitive endoderm cells. Our detailed roadmap on polarization, compaction, position and lineage segregation events during human preimplantation development paves the road for further functional studies. Fundamental knowledge of lineage segregation events will eventually explain how and why embryos fail to develop further before or during implantation.

/pdf/lineage-segregation-in-human-pre-implantation-embryos-is-lelp75ma.pdf

Lineage segregation in human pre-implantation embryos is specified by YAP1 and TEAD1

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BMP4 plays a role in apoptosis during human preimplantation development.

Effects of PER3 clock gene polymorphisms on aging-related changes of the cerebral cortex.

Lineage segregation in human pre-implantation embryos is specified by YAP1 and TEAD1