Early Human Embryos Research Articles

Systems based analysis of human embryos and gene networks involved in cell lineage allocation

BackgroundLittle is understood of the molecular mechanisms involved in the earliest cell fate decision in human development, leading to the establishment of the trophectoderm (TE) and inner cell mass (ICM) stem cell population. Notably, there is a lack of understanding of how transcriptional networks arise during reorganisation of the embryonic genome post-fertilisation.ResultsWe identified a hierarchical structure of preimplantation gene network modules around the time of embryonic genome activation (EGA). Using network models along with eukaryotic initiation factor (EIF) and epigenetic-associated gene expression we defined two sets of blastomeres that exhibited diverging tendencies towards ICM or TE. Analysis of the developmental networks demonstrated stage specific EIF expression and revealed that histone modifications may be an important epigenetic regulatory mechanism in preimplantation human embryos. Comparison to published RNAseq data confirmed that during EGA the individual 8-cell blastomeres are transcriptionally primed for the first lineage decision in development towards ICM or TE.ConclusionsUsing multiple systems biology approaches to compare developmental stages in the early human embryo with single cell transcript data from blastomeres, we have shown that blastomeres considered to be totipotent are not transcriptionally equivalent. Furthermore we have linked the developmental interactome to individual blastomeres and to later cell lineage. This has clinical implications for understanding the impact of fertility treatments and developmental programming of long term health.

Molecular aspects of aneuploidy in preimplantation human embryos: a mini-review

Aneuploidy is a major obstacle in achieving successful pregnancies in in vitro fertilization (IVF) procedures. In practice, more than 50% of preimplantation embryos are aneuploid and unable to achieve viable pregnancy. Analysis of human sperm and oocytes has showed that aneuploidy in preimplantation embryos is predominantly caused by an error-prone meiotic chromosome segregation mechanism in oocytes. In reproductive aged women, aneuploidy rate in human oocytes is reaching 20–30%, in contrast to human sperm, that only 1–8% have an abnormal chromosomal content. Meiotic aneuploidy can occur from meiosis I (MI) non-disjunction, meiosis II (MII) non-disjunction and MI or MII pre-division. Multiple factors have been suggested to contribute to meiotic aneuploidy including maternal age and impaired cohesin complex formation. Maternal age is the major critical factor related to aneuploidy; 50% of the oocytes from advanced age women (≥40 years old) are aneuploid due to meiotic errors. The relationship between maternal age and altered recombination, which is entirely dependent on the context of chromosomes, can also contribute to development of aneuploidy. Genomic errors can also arise during post-fertilization mitotic divisions, resulting in embryonic mosaicism. The mechanisms leading to embryonic mosaicism during embryonic mitosis are; non-disjunction, anaphase lagging and endoreplication. Mosaicism exists in ~15–90% of all cleavage stage human embryos and in general, mitotic aneuploidies rise from 63% at the cleavage stage to 95% in blastocyst stage. Relaxation or absence of cell cycle checkpoints are possible mechanisms that have been hypothesized to account for mitotic aneuploidy in early human preimplantation embryos. Specifically, defects in spindle assembly checkpoint (SAC) and malfunction of cohesion complexes, can lead to premature chromosome separation, while delay in their removal may result in non-disjunction. Furthermore, extra-nuclear DNA formation generated from lagging chromosomes with severe DNA damage (i.e., micronucleation), may be a major mechanism of mitotic aneuploidy. Once source of aneuploidy involves paternal factor is related to mitotic aneuploidy, as severe sperm defects and advanced paternal age can increase the percentage of mitotic abnormalities in embryos. Further work and analysis into the molecular mechanisms that lead to meiotic and mitotic aneuploidy in preimplantation embryos, could inspire clinical strategies to reduce the occurrence of aneuploidy and consequently improve the success rates of IVF.

Test-tube embryos - mouse and human development in vitro to blastocyst stage and beyond.

Mammalian embryogenesis is intrauterine and depends on support from the maternal environment. Therefore, in order to directly study and manipulate early mouse and human embryos, fine-tuned culture conditions have to be provided to maintain embryo growth in vitro. Over time, the establishment and implementation of embryo culture methods have come a long way, initially enabling the development of few pre-implantation stages, expanding later to support in vitro embryogenesis from fertilization until blastocyst and even ex utero development beyond the implantation stages. Designing culture conditions that enable near physiological development of early embryos without maternal input, especially during the peri- and post-implantation stages, requires overcoming numerous experimental challenges, and it is still far from optimal. Nevertheless, embryo culture methods are an essential cornerstone of both assisted reproductive technologies and basic research, and these methods provide a platform to understand life's greatest miracle - the development of a new organism.

Organoids: Avatars for Personalized Medicine.

Stem cells are the foundation of all mammalian life. Stem cells build and maintain our bodies throughout life. Two types of stem cells are discerned.1) Embryonic stem cells (ES cells) are briefly present in the early human or mouse embryo, a few days after fertilization. These ES cells can be grown indefinitely in the lab and have the potential to build each and every tissue in our body. Because of this 'pluripotency', ES cells hold great promise for therapeutic application in the field of regenerative medicine. It is also possible to take skin cells (or other cells) from adults and convert these in the lab into cells with ES properties, so called iPS cells. Many of the hurdles that ES cell technology have faced, do not exist for iPS cells.2) Adult stem cells. Every organ in our body is believed to harbor its own dedicated stem cells. These adult stem cells replace tissue that is lost due to wear and tear, trauma and disease. Adult stem cells are highly specialized and can only produce the tissue in which they reside; they are 'multipotent'. Examples are bone marrow stem cells that make all blood cells, skin stem cells and gut stem cells. Even the brain is now known to harbor its specialized stem cells. The adult stem cells allow us to live 80-90 years, but this comes at a cost: they are the cells that most easily transform into cancer cells.Both types of stem cells can be used to establish 'organoids', 3D structures established in a dish, that recapitulate many aspects of the organ they represent. Pluripotent stem cells can be taken through the developmental steps that establish organs during embryogenesis. This has worked particularly well for parts of the the central nervous system, the kidney and GI organs. We have shown that adult epithelial stem cells carrying the generic Lgr5 marker can be cultured under tissue-repair conditions and generate epithelial organoids directly from healthy and diseased organs such as the gut, the liver, the lung and the pancreas. Organoid technology opens a range of avenues for the study of development, physiology and disease, for drug development and for personalized medicine. In the long run, cultured mini-organs may replace transplant organs from donors and hold promise in gene therapy.

Single-Cell Multi-omics Sequencing of Human Early Embryos

(Abstracted from Nat Cell Biol 2018;20:847–858) DNA methylation and chromatin states are critical epigenetic indicators in embryogenesis that have been extensively studied during mouse preimplantation development. DNA methylation dynamics and parental allele-specific DNA methylation in human preimplantation embryos have been analyzed thoroughly; however, chromatin remodeling, parental allele-specific chromatin accessibility, and interrelationships between these omics are not well understood.

1 Whole-genome bisulfite sequencing of bovine gametes and invivo-produced pre-implantation embryos

Dynamic changes in DNA methylation are crucial in the epigenetic regulation of mammalian embryogenesis. Global DNA methylation studies in the bovine, however, remain mostly at the immunostaining level. We adopted the single-cell whole-genome bisulfite sequencing method to characterise stage-specific genome-wide DNA methylation in bovine sperm, individual oocytes derived invivo and invitro, and invivo-developed embryos at the 2-, 4-, 8-, and 16-cell stages. This method allowed us to theoretically cover all CpG sites in the genome using a limited number of cells from single embryos. Pools of 20 sperm were selected from a bull with proven fertility. Single oocytes (n=6) and embryos (n=4 per stage) were collected from Holstein cows (n=10). Single-cell whole-genome bisulfite sequencing libraries were prepared and sequenced using the Illumina HiSEqn 4000 platform (Illumina, San Diego, CA, USA). Sequencing reads were filtered and aligned to the bovine reference genome (UMD 3.1.1) using Bismark (Krueger and Andrews 2011Bioinformatics27, 1571-1572, DOI: 10.1093/bioinformatics/btr167).A 300-bp tile-based method was applied to bin the genome into consecutive windows to facilitate comparison across samples. The DNA methylation level was calculated as the fraction of read counts of the total number of cytosines (methylated) in the total read counts of reported cytosines and thymines (methylated and unmethylated), only if more than 3 CpG sites were covered in this tile. Gamete-specific differentially methylated regions were identified when DNA methylation levels were greater than 75% in one type of gamete and less than 25% in the other with false discovery rate-corrected Fisher’s exact test P-values of less than 0.05. The major wave of genome-wide DNA demethylation was complete at the 8-cell stage when de novo methylation became prominent. Sperm and oocytes had numerous differentially methylated regions that were enriched in intergenic regions. Differentially methylated regions were also identified between invivo- and invitro-matured oocytes. Moreover, X chromosome methylation followed the global dynamic patterns. Virtually no (less than 1.5%) DNA methylation was found in mitochondrial DNA. Finally, using our RNA sequencing data generated from the same developmental stages (Jiang et al. 2014 BMC Genomics 15, 756; DOI: 10.1186/1471-2164-15-756), we revealed an inverse correlation between gene expression and promoter methylation. Our study provides the first fully comprehensive analysis of the global dynamics of DNA methylation in bovine gametes and single early embryos using single-cell whole-genome bisulfite sequencing. These data provide insights into the critical features of the methylome of bovine embryos and serve as an important reference for embryos produced by assisted reproduction, such as IVF and cloning, and a model for human early embryo epigenetic regulation.

Correction to 'DNA methylation subpatterns at distinct regulatory regions in human early embryos'.

Open AccessMoreSectionsView PDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail Cite this article Luo Rongsong, Bai Chunling, Yang Lei, Zheng Zhong, Su Guanghua, Gao Guangqi, Wei Zhuying, Zuo Yongchun and Li Guangpeng 2018Correction to ‘DNA methylation subpatterns at distinct regulatory regions in human early embryos’Open Biol.8180215180215http://doi.org/10.1098/rsob.180215SectionOpen AccessCorrectionsCorrection to ‘DNA methylation subpatterns at distinct regulatory regions in human early embryos’ Rongsong Luo Rongsong Luo http://orcid.org/0000-0002-1822-8260 Google Scholar Find this author on PubMed Search for more papers by this author , Chunling Bai Chunling Bai Google Scholar Find this author on PubMed Search for more papers by this author , Lei Yang Lei Yang Google Scholar Find this author on PubMed Search for more papers by this author , Zhong Zheng Zhong Zheng Google Scholar Find this author on PubMed Search for more papers by this author , Guanghua Su Guanghua Su Google Scholar Find this author on PubMed Search for more papers by this author , Guangqi Gao Guangqi Gao Google Scholar Find this author on PubMed Search for more papers by this author , Zhuying Wei Zhuying Wei Google Scholar Find this author on PubMed Search for more papers by this author , Yongchun Zuo Yongchun Zuo Google Scholar Find this author on PubMed Search for more papers by this author and Guangpeng Li Guangpeng Li Google Scholar Find this author on PubMed Search for more papers by this author Rongsong Luo Rongsong Luo http://orcid.org/0000-0002-1822-8260 Google Scholar Find this author on PubMed Search for more papers by this author , Chunling Bai Chunling Bai Google Scholar Find this author on PubMed Search for more papers by this author , Lei Yang Lei Yang Google Scholar Find this author on PubMed Search for more papers by this author , Zhong Zheng Zhong Zheng Google Scholar Find this author on PubMed Search for more papers by this author , Guanghua Su Guanghua Su Google Scholar Find this author on PubMed Search for more papers by this author , Guangqi Gao Guangqi Gao Google Scholar Find this author on PubMed Search for more papers by this author , Zhuying Wei Zhuying Wei Google Scholar Find this author on PubMed Search for more papers by this author , Yongchun Zuo Yongchun Zuo Google Scholar Find this author on PubMed Search for more papers by this author and Guangpeng Li Guangpeng Li Google Scholar Find this author on PubMed Search for more papers by this author Published:05 December 2018https://doi.org/10.1098/rsob.180215Open Biol.8, 180131. (Published online 31 October 2018). (doi:10.1098/rsob.180131)The p-value of significance test has been given as ‘p < 0.5’ in the Material and methods section (4.4), which is incorrect.The correct writing for the p-value is ‘p < 0.05’. It should be noted that we correctly wrote the p-value in the electronic supplementary materials and in responding to the reviewers' comments, i.e. ‘p < 0.05’.All the authors gave their consent to this correction. Previous Article VIEW FULL TEXT DOWNLOAD PDF FiguresRelatedReferencesDetailsCited by Lin Y, Li Y, Zhu X, Huang Y, Li Y and Li M (2019) Genetic Contexts Characterize Dynamic Histone Modification Patterns Among Cell Types, Interdisciplinary Sciences: Computational Life Sciences, 10.1007/s12539-019-00338-7, 11:4, (698-710), Online publication date: 1-Dec-2019. This IssueDecember 2018Volume 8Issue 12 Article InformationDOI:https://doi.org/10.1098/rsob.180215PubMed:30518639Published by:Royal SocietyOnline ISSN:2046-2441History: Published online05/12/2018 License:© 2018 The Authors.Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Citations and impact

Overview of Preimplantation Genetic Diagnosis (PGD): Historical Perspective and Future Direction.

Preimplantation genetic diagnosis (PGD) can be considered the earliest form of prenatal testing. It was first used in humans over 26years ago. At its inception, PGD could only be performed for a limited number of genetic disorders. Technological advances in molecular biology and cytogenomics have been utilized in the field of PGD to greatly expand the spectrum of genetic disorders that can now be detected in early human embryos.

Systematic Review of Ovarian Activity and Potential for Embryo Formation and Loss during the Use of Hormonal Contraception.

For this study, the authors looked at English-language research articles that focused on how hormonal birth control, such as the birth control pill, may affect very early human embryos. The authors found that abnormal ovulation, or release of an egg followed by abnormal hormone levels, may often occur in women using hormonal birth control. This may increase the number of very early human embryos who are lost before a pregnancy test becomes positive. For women who are thinking about using hormonal birth control, this is important information to consider.

Ética de las intervenciones sobre el embrión preimplantado

The Author describes briefly how, through the confluence of trie new medical specialties of Reproductive Medicine and Molecular Genetics, a wide avenue has been opened to the genetic diagnosis and therapy of the preimplantation embryo. Today, the human embryo in its early stages has become the object of medical experimentation. In the next future, we will see the advent of new techniques for microsurgical manipulation and gene therapy Embryo-fetal Medicine will grow actively. &#x0D; The Author, after briefly analyzing the origin, and criticizing the meaning, of the term preembryo, condueles, on the basis of unbiased observation of the continuum of human life, that only an attitude of respect for life and the determination to extend to the early human embryo the benefits of (gene)therapy are consistent with the deepest medical-deontological traditions.

DNA methylation subpatterns at distinct regulatory regions in human early embryos.

DNA methylation has been investigated for many years, but recent technologies have allowed for single-cell- and single-base-resolution DNA methylation datasets and more accurate assessment of DNA methylation dynamics at the key genomic regions that regulate gene expression in human early embryonic development. In this study, the region from upstream 20 kb to downstream 20 kb of RefSeq gene was selected and divided into 12 distinct regions (up20, up10, up5, up2, 5'UTR, exon, intron, 3'UTR, down2, down5, down10 and down20). The candidate promoter region (TSS ± 2 kb) was further divided into 20 consecutive subregions, which were termed ‘bins’. The DNA methylation dynamics of these regions were systematically analysed along with their effects on gene expression in human early embryos. The dynamic DNA methylation subpatterns at the distinct genomic regions with a focus on promoter regions were mapped. For the 12 distinct genomic regions, up2 and 5'UTR had the lowest DNA methylation levels, and their methylation dynamics were different with other regions. The region 3'UTR had the highest DNA methylation levels, and the correlation analysis with gene expression proved that it was a feature of transcribed genes. For the 20 bins in promoter region, the CpG densities showed a normal distribution pattern, and the trend of the methylated CpG counts was inverse with the DNA methylation levels, especially for the bin 1 (downstream 200 bp of the TSS). Through the correlation analysis between DNA methylation and gene expression, the current study finally revealed that the region bin −4 to 6 (800 bp upstream to 1200 bp downstream of the TSS) was the best candidate for the promoter region in human early embryos, and bin 1 was the putative key regulator of gene activity. This study provided a global and high-resolution view of DNA methylation subpatterns at the distinct genomic regions in human early embryos.

A hybrid approach for multiple blastomeres identification in early human embryo images

Automatic quality assessment of the human embryo paves the way to improve the outcome of the In Vitro Fertilization (IVF) treatment by selecting embryos with the highest implantation potentials. Analyzing the shape, size, and motion of the cells, as well as other time-related changes, facilitates embryo quality assessment. However, the ambitious 3D-like side-lit appearance of the embryo, occlusion, transparency of cells and artifacts such as fragmentation make automatic detection of blastomeres (embryonic cells) a challenging task. In this paper, an automated noninvasive approach is proposed to identify multiple blastomere cells inside an embryo at different growth stages. In particular, the proposed method aims to identify up to 8 blastomeres in microscopic human embryo images of days 1–3. The proposed system is a hybrid approach that aggregates both models and features capturing global and local characteristics to locate the boundaries of each blastomere. Experimental results on a large dataset of 271 embryo images with various blastomere numbers and sizes confirm that the proposed method identifies blastomeres with average Precision, Recall, and Overall Quality of 85.9%, 85.3%, and 76.5%, respectively.

DNA methylation reprogramming of functional elements during mammalian embryonic development

DNA methylation plays important roles during development. However, the DNA methylation reprogramming of functional elements has not been fully investigated during mammalian embryonic development. Herein, using our modified MethylC-Seq library generation method and published post-bisulphite adapter-tagging (PBAT) method, we generated genome-wide DNA methylomes of human gametes and early embryos at single-base resolution and compared them with mouse methylomes. We showed that the dynamics of DNA methylation in functional elements are conserved between humans and mice during early embryogenesis, except for satellite repeats. We further found that oocyte-specific hypomethylated promoters usually exhibit low CpG densities. Genes with oocyte-specific hypomethylated promoters generally show oocyte-specific hypomethylated genic and intergenic regions, and these hypomethylated regions contribute to the hypomethylation pattern of mammalian oocytes. Furthermore, hypomethylated genic regions with low CG densities correlate with gene silencing in oocytes, whereas hypomethylated genic regions with high CG densities correspond to high gene expression. We further show that methylation reprogramming of enhancers during early embryogenesis is highly associated with the development of almost all human organs. Our data support the hypothesis that DNA methylation plays important roles during mammalian development.

Deconstructing and reconstructing the mouse and human early embryo.

The emergence of form and function during mammalian embryogenesis is a complex process that involves multiple regulatory levels. The foundations of the body plan are laid throughout the first days of post-implantation development as embryonic stem cells undergo symmetry breaking and initiate lineage specification, in a process that coincides with a global morphological reorganization of the embryo. Here, we review experimental models and how they have shaped our current understanding of the post-implantation mammalian embryo.

Comparison between paraffin and mineral oil covering on early human embryo culture: a prospective randomized study

ABSTRACTThe oil overlay in microdrop culture systems prevents medium evaporation, helps to maintain appropriate pH and osmotic conditions and protects from microbial contamination. In the present study, we prospectively compared covering by Ovoil™, a paraffin oil, and LiteOil®, a mineral oil, on the in vitro development of human embryos and their suitability for transfer/freezing at day 3 and live birth rate. One hundred and one patients undergoing in vitro fertilization (IVF) treatment by intracytoplasmic sperm injection (ICSI) were enrolled in our study. After ICSI, 1237 oocytes were 1:1 randomly allocated into 2 groups according to the type of overlaying oil: Ovoil™ (616 oocytes) or LiteOil® (621 oocytes). Fertilization rate was assessed around 18 hours post-insemination (hpi) and embryos were checked for early cleavage at 25 hpi. Embryo morphology was recorded on days 2 and 3. A total of 437 (Ovoil™) and 438 day 3 embryos (LiteOil®) were analyzed. There were no differences between the two groups in terms of fertilization rate and occurrence of early cleavage. The proportion of top quality embryos (41.7% vs. 41.2%) and the final utilization rates (92.2% vs. 92.0%) were similar in Ovoil and LiteOil groups, respectively, at day 3. Live birth rate per transfer was essentially the same with Ovoil™ overlay (26.9%) when compared to LiteOil® (26.2%). Live birth rate in patients who simultaneously received embryos from both overlay types was 17.2%. Despite the different characteristics of these two oils regarding hydrocarbon saturation, packing and temperature storage, Ovoil™ and LiteOil® can be used in parallel in the same IVF protocol.Abbreviations: ART: assisted reproductive technologies; hpi: hours post-insemination; hSA: human serum albumin; HTF: human tubal fluid; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; MII: metaphase II; MEA: mouse embryo assay; RT: room temperature.

Establishment of environmentally sensitive DNA methylation states in the very early human embryo.

The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype.

Single-cell multi-omics sequencing of human early embryos.

DNA methylation, chromatin states and their interrelationships represent critical epigenetic information, but these are largely unknown in human early embryos. Here, we apply single-cell chromatin overall omic-scale landscape sequencing (scCOOL-seq) to generate a genome-wide map of DNA methylation and chromatin accessibility at single-cell resolution during human preimplantation development. Unlike in mice, the chromatin of the paternal genome is already more open than that of the maternal genome at the mid-zygote stage in humans, and this state is maintained until the 4-cell stage. After fertilization, genes with high variations in DNA methylation, and those with high variations in chromatin accessibility, tend to be two different sets. Furthermore, 1,797 out of 5,155 (35%) widely open chromatin regions in promoters closed when transcription activity was inhibited, indicating a feedback mechanism between transcription and open chromatin maintenance. Our work paves the way for dissecting the complex, yet highly coordinated, epigenetic reprogramming during human preimplantation development.

The oocyte-early embryo-specific subcortical maternal complex in mammals

Prior to zygotic genome activation, gene transcription is quiescent. The programs of the early embryonic development are mainly regulated by maternal-effect genes. The research of mammalian maternal-effect genes has long been hindered due to the limitation of research materials and techniques. Recently, a subcortical maternal complex (SCMC) was identified specifically in mammalian oocytes and preimplantation embryos. The SCMC is a protein complex consisting of numerous maternal effect proteins, and is required for mouse preimplantation development. Accumulating evidence suggests that SCMC can be used to identify new maternal-effect genes, to clarify the molecular mechanism of other maternal-effect genes, and to explore the regulation of early embryonic development in mammals. Additionally, the SCMC may be conserved in human oocytes and early embryos. Importantly, the mutations of human SCMC genes are associated with several human reproductive disorders. Collectively, these findings indicate that the SCMC may be an important module orchestrating the maternal-to-zygotic transition in mammalian early development. Further investigations of the SCMC will greatly promote the understanding of molecular regulation in mammalian early development, significantly contributing to human reproductive medicine.

Holoprosencephaly in the genomics era.

Holoprosencephaly (HPE) is the direct consequence of specific genetic and/or environmental insults interrupting the midline specification of the nascent forebrain. Such disturbances can lead to a broad range of phenotypic consequences for the brain and face in humans. This malformation sequence is remarkably common in utero (1 in 250 human fetuses), but 97% typically do not survive to birth. The precise molecular pathogenesis of HPE in these early human embryos remains largely unknown. Here, we outline our current understanding of the principal driving factors leading to HPE pathologies and elaborate our multifactorial integrated genomics approach. Overall, our understanding of the pathogenesis continues to become simpler, rather than more complicated. Genomic technologies now provide unprecedented insight into disease-associated variation, including the overall extent of genetic interactions (coding and noncoding) predicted to explain divergent phenotypes.

New insights into human early embryo development: a particular theoretical study

The experimental research on the subject of human early embryo development has been remained insufficient because of ethical norms and legal constraints. In this context, the carrying out of theoretical studies could speed up the slow knowledge progression on this subject. Thus, I present here a particular model of theoretical study based on a synthesis of selected published experimental results combined with what has been provided from my interpretation of scientific signs masked in some Qur‟an verses. In the obtained detailed scenario, I consider that the third cleavage, resulting in 8 blastomeres, is coupled to a particular rearrangement in which 2 daughter cells seem move down and 2 others move up; while the 4 remaining cells seem stay at their initial position (I called them “4 HI cells”). Nevertheless, I consider that the fourth cleavage, resulting in 16 blastomeres, is coupled to a rearrangement that gives the impression of a harmonious descent: in fact, one of each two daughter cells seems pushed down. This descent materializes a morula top–bottom axis, which will go to coincide with the embryo-abembryo axis of the blastocyst. Just after this fourth cleavage, during a polarization process, the nucleuses of the entire 16 cells move towards a basal region. I consider the polarized 16 cells as the precursors of all the Troph-Ectoderm (TE cells), whilst acknowledging that the 4 HI cells are at once precursors of TE cells and the Inner Cell Mass (ICM). Moreover, in this study I evoke, for the first time, the possible contribution of the microvilli of some outer cell surfaces to the guidance and move of the early human embryo all along the oviduct and during the initiate steps of its implantation in the endometrium. At the end I contribute to the classification of the concept of knowledge and I show how this study represents a model of fruitful exchanges between philosophy, science and religion. Key words : Human early embryo development - Troph-Ectoderm (TE cells) - 16 blastomere stage - Morula / blastocyst axis - Microvilli - Early embryo transport - Initiation of implantation - Knowledge definition - Qur‟an scientific signs - Philosophy, science and religion – Dynamism of Holy Qur‟an