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Implantation initiation of self-assembled embryo-like structures generated using three types of mouse blastocyst-derived stem cells.

ABSTRACT: Spatially ordered embryo-like structures self-assembled from blastocyst-derived stem cells can be generated to mimic embryogenesis in vitro. However, the assembly system and developmental potential of such structures needs to be further studied. Here, we devise a nonadherent-suspension-shaking system to generate self-assembled embryo-like structures (ETX-embryoids) using mouse embryonic, trophoblast and extra-embryonic endoderm stem cells. When cultured together, the three cell types aggregate and sort into lineage-specific compartments. Signaling among these compartments results in molecular and morphogenic events that closely mimic those observed in wild-type embryos. These ETX-embryoids exhibit lumenogenesis, asymmetric patterns of gene expression for markers of mesoderm and primordial germ cell precursors, and formation of anterior visceral endoderm-like tissues. After transplantation into the pseudopregnant mouse uterus, ETX-embryoids efficiently initiate implantation and trigger the formation of decidual tissues. The ability of the three cell types to self-assemble into an embryo-like structure in vitro provides a powerful model system for studying embryogenesis.

SUBMITTER: Zhang S

PROVIDER: S-EPMC6353907 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Implantation initiation of self-assembled embryo-like structures generated using three types of mouse blastocyst-derived stem cells.

Zhang Shaopeng S Chen Tianzhi T Chen Naixin N Gao Dengfeng D Shi Bingbo B Kong Shuangbo S West Rachel Claire RC Yuan Ye Y Zhi Minglei M Wei Qingqing Q Xiang Jinzhu J Mu Haiyuan H Yue Liang L Lei Xiaohua X Wang Xuepeng X Zhong Liang L Liang Hui H Cao Suying S Belmonte Juan Carlos Izpisua JCI Wang Haibin H Han Jianyong J

Nature communications 20190130 1

Spatially ordered embryo-like structures self-assembled from blastocyst-derived stem cells can be generated to mimic embryogenesis in vitro. However, the assembly system and developmental potential of such structures needs to be further studied. Here, we devise a nonadherent-suspension-shaking system to generate self-assembled embryo-like structures (ETX-embryoids) using mouse embryonic, trophoblast and extra-embryonic endoderm stem cells. When cultured together, the three cell types aggregate a ...[more]

PMID: 30700702

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Project description:In mammalian embryonic development, blastocyst hatching is essential for normal implantation and development of the fetus. We reported previously that blastocysts hatching out of the zona pellucida (ZP) exhibited site preferences that were associated with pregnancy outcomes. To characterize these site differences, we analyzed the transcriptomes in the following developing mouse blastocysts within 16 h of hatching: expanding (E), hatching from the A-site (A), B-site (B), and C-site (C), hatched (H), and non-hatching (N). By principal component analysis and hierarchical cluster analysis, we determined that the gene expression profiles of A and B blastocysts, which resulted in good fertility, clustered closely. C and N blastocysts, which resulted in poor fertility, clustered closely, but distantly from A and B. Embryos hatched at B- vs. C-sites, with good vs. poor pregnancy, showed 178 differentially expressed genes (DEGs), mainly involved in immunity, which correlated positively with birth rate. These DEGs were primarily regulated by transcription factors TCF24 and DLX3. During blastocyst hatching, immune-related genes were regulated, such as Ptgs1, Lyz2, Il-α, Cfb (upregulated) and Cd36 (downregulated). By immunofluorescence staining, we found C3 and IL-1β on the extra-luminal surface of the trophectoderm of the hatched blastocyst, suggesting that they play a role in maternal-fetal interactions. As the blastocysts developed from the expanding to the fully hatched state, 307 DEGs were either upregulated by transcription factor ATOH8 or downregulated by SPIC to switch on immune pathways. Based on the hatching outcome, we identified three transcription patterns in developing blastocysts, with complex changes in the transcriptional regulation network of failed hatched blastocysts vs. successfully hatched blastocysts. We developed a LASSO regression-based model using DEGs Lyz2, Cd36, Cfb, and Cyp17a1 to predict implantation success. This study revealed the diverse, multidimensional developmental fates of blastocysts during short-term hatching and indicated that the immune properties of the embryo had a major effect on blastocyst hatching outcomes. We suggest that transcriptional changes and their regulation during the development of the preimplantation blastocyst affect implantation. This study contributes to our understanding of the role of transcriptional changes in mammalian embryonic development during hatching and their effect on maternal-fetal interactions.

Project description:CRENKA [Cys-Arg-(NMe)Glu-Lys-Ala, where (NMe)Glu refers to N-methyl-Glu], an anti-cancer pentapeptide that induces prostate tumor necrosis and significant reduction in tumor growth, was engineered to increase the resistance to endogenous proteases of its parent peptide, CREKA (Cys-Arg-Glu-Lys-Ala). Considering their high tendency to aggregate, the self-assembly of CRENKA and CREKA into well-defined and ordered structures has been examined as a function of peptide concentration and pH. Spectroscopic studies and atomistic molecular dynamics simulations reveal significant differences between the secondary structures of CREKA and CRENKA. Thus, the restrictions imposed by the (NMe)Glu residue reduce the conformational variability of CRENKA with respect to CREKA, which significantly affects the formation of well-defined and ordered self-assembly morphologies. Aggregates with poorly defined morphology are obtained from solutions with low and moderate CREKA concentrations at pH 4, whereas well-defined dendritic microstructures with fractal geometry are obtained from CRENKA solutions with similar peptide concentrations at pH 4 and 7. The formation of dendritic structures is proposed to follow a two-step mechanism: (1) pseudo-spherical particles are pre-nucleated through a diffusion-limited aggregation process, pre-defining the dendritic geometry, and (2) such pre-nucleated structures coalesce by incorporating conformationally restrained CRENKA molecules from the solution to their surfaces, forming a continuous dendritic structure. Instead, no regular assembly is obtained from solutions with high peptide concentrations, as their dynamics is dominated by strong repulsive peptide-peptide electrostatic interactions, and from solutions at pH 10, in which the total peptide charge is zero. Overall, results demonstrate that dendritic structures are only obtained when the molecular charge of CRENKA, which is controlled through the pH, favors kinetics over thermodynamics during the self-assembly process.

Dataset Information

Implantation initiation of self-assembled embryo-like structures generated using three types of mouse blastocyst-derived stem cells.

Publications

Implantation initiation of self-assembled embryo-like structures generated using three types of mouse blastocyst-derived stem cells.

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