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

Meistermann, Dimitri; Bruneau, Alexandre; Loubersac, Sophie; Reignier, Arnaud; Firmin, Julie; François-Campion, Valentin; Kilens, Stéphanie; Lelièvre, Yohann; Lammers, Jenna; Feyeux, Magalie; Hulin, Phillipe; Nédellec, Steven; Bretin, Betty; Castel, Gaël; Allègre, Nicolas; Covin, Simon; Bihouée, Audrey; Soumillon, Magali; Mikkelsen, Tarjei S.; Barrière, P.; Chazaud, Claire; Chappell, Joel; Pasque, Vincent; Bourdon, Jérémie; Fréour, Thomas; David, Laurent

doi:10.1016/j.stem.2021.04.027

Cited by 122 publications

(203 citation statements)

References 87 publications

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“…At 4 dpf, the conceptus forms a morula that initiates cavitation to make a blastocyst. Blastocyst development (at 5–7 dpf) supports the generation of the three founding lineages 11 : the epiblast (EPI), which is embryonic; trophectoderm (TE), which is extraembryonic; and primitive endoderm (PrE), which is extraembryonic (Fig. 1a ).…”

Section: Inhibition Of Hippo Erk and Tgfβ Pathwaysmentioning

confidence: 76%

“…4a ). Furthermore, trophoblasts were enriched in blastocyst-stage TE transcripts 11 ( ESRRB , GRHL1 , OVOL1 , GATA2 , GATA3 , TBX3 , KRT19 , CGA , CGB5 and CGB7 ) but not in some post-implantation trophoblast markers 11 ( SIGLEC6 and DPP4 ) (Extended Data Fig. 4b, c ).…”

Section: Formation Of Blastocyst-stage Analoguesmentioning

confidence: 99%

“…1e, f ) to ranges similar to those for 5–7 dpf blastocysts 17 (stages B3 to B6). TE cell analogues 11 (identified as GATA2 + GATA3 + CDX2 + TROP2 + ) formed, proliferated (Fig. 1f–h , Extended Data Fig.…”

Section: Inhibition Of Hippo Erk and Tgfβ Pathwaysmentioning

confidence: 99%

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Human blastoids model blastocyst development and implantation

Kagawa

Javali

Khoei

et al. 2021

Nature

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One week after fertilization, human embryos implant into the uterus. This event requires the embryo to form a blastocyst consisting of a sphere encircling a cavity lodging the embryo proper. Stem cells can form a blastocyst model that we called a blastoid1. Here we show that naive human pluripotent stem cells cultured in PXGL medium2 and triply inhibited for the Hippo, TGF-β and ERK pathways efficiently (with more than 70% efficiency) form blastoids generating blastocyst-stage analogues of the three founding lineages (more than 97% trophectoderm, epiblast and primitive endoderm) according to the sequence and timing of blastocyst development. Blastoids spontaneously form the first axis, and we observe that the epiblast induces the local maturation of the polar trophectoderm, thereby endowing blastoids with the capacity to directionally attach to hormonally stimulated endometrial cells, as during implantation. Thus, we propose that such a human blastoid is a faithful, scalable and ethical model for investigating human implantation and development3,4.

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Section: Inhibition Of Hippo Erk and Tgfβ Pathwaysmentioning

confidence: 76%

Section: Formation Of Blastocyst-stage Analoguesmentioning

confidence: 99%

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Human blastoids model blastocyst development and implantation

Kagawa

Javali

Khoei

et al. 2021

Nature

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“…Technologies for unbiased and integrated multi-omics across transcriptome, epigenome, proteome and metabolome analysis of single or small numbers of cells are advancing and suited to early embryo screening for DOHaD candidates [139][140][141]. Omics technologies are required for assessing human embryo competence in relation to diverse environments, such as culture composition [142][143][144], and also across time/maturation of the embryo [145].…”

Section: Conclusion and Thinking Aheadmentioning

confidence: 99%

Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk

Fleming

Sun

Denisenko

et al. 2021

IJERPH

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Environment around conception can influence the developmental programme with lasting effects on gestational and postnatal phenotype and with consequences for adult health and disease risk. Peri-conception exposure comprises a crucial part of the ‘Developmental Origins of Health and Disease’ (DOHaD) concept. In this review, we consider the effects of maternal undernutrition experienced during the peri-conception period in select human models and in a mouse experimental model of protein restriction. Human datasets indicate that macronutrient deprivation around conception affect the epigenome, with enduring effects on cardiometabolic and neurological health. The mouse model, comprising maternal low protein diet exclusively during the peri-conception period, has revealed a stepwise progression in altered developmental programming following induction through maternal metabolite deficiency. This progression includes differential effects in extra-embryonic and embryonic cell lineages and tissues, leading to maladaptation in the growth trajectory and increased chronic disease comorbidities. The timeline embraces an array of mechanisms across nutrient sensing and signalling, cellular, metabolic, epigenetic and physiological processes with a coordinating role for mTORC1 signalling proposed. Early embryos appear active participants in environmental sensing to optimise the developmental programme for survival but with the trade-off of later disease. Similar adverse health outcomes may derive from other peri-conception environmental experiences, including maternal overnutrition, micronutrient availability, pollutant exposure and assisted reproductive treatments (ART) and support the need for preconception health before pregnancy.

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“…Amongst the most highly upregulated marker genes was ENPEP , the gene for a surface marker (APA) that marks trophectoderm progenitor cells capable of forming STB 9, 66 ; ABCG2 , a plasma membrane transporter highly expressed in trophectoderm and human placenta 5, 67 ; TP63 , a p53 family member defining the CTB stem cell compartment 5, 68 . Well known transcription factors specifying trophectoderm lineage, CDX2 69, 70 , GATA3 9, 70, 71 , MSX2 72 , NR2F2 73 were also specifically upregulated in EZH2i treated naïve hESCs (Fig. 5b-e).…”

Section: Resultsmentioning

confidence: 85%

Polycomb Repressive Complex 2 shields naïve human pluripotent cells from trophectoderm differentiation

Kumar

Navarro

Winblad

et al. 2021

Preprint

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The first lineage choice made in human embryo development separates trophectoderm from the inner cell mass, which proceeds to form the pluripotent epiblast and primitive endoderm. Trophectoderm on the other hand gives rise to the placenta. Naïve pluripotent stem cells are derived from the pluripotent epiblast of the blastocyst and offer possibilities to explore how lineage integrity is maintained. Here, we discover that Polycomb repressive complex 2 (PRC2) restricts an intrinsic capacity of naïve pluripotent stem cells to give rise to trophectoderm. Through quantitative epigenome profiling, we find that broad histone H3 lysine 27 trimethylation (H3K27me3) hypermethylation is a common feature of naïve pluripotency across species. We define a previously unappreciated, naïve-specific set of bivalent promoters, featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm transcription factors in a transcriptionally poised state that is resolved to an active state upon depletion of H3K27me3 via inhibition of the enzymatic subunits of PRC2, EZH1/2. Conversely, primed human embryonic stem cells cannot be driven towards trophectoderm development via PRC2 inhibition. While naïve and primed hESCs share the majority of bivalent promoters, PRC2 contributes to the repression of largely non-overlapping subsets of these promoters in each state, hence H3K27me3-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.

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

Cited by 122 publications

References 87 publications

Human blastoids model blastocyst development and implantation

Human blastoids model blastocyst development and implantation

Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk

Polycomb Repressive Complex 2 shields naïve human pluripotent cells from trophectoderm differentiation

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