Human pre-implantation embryo development

Abstract

SummaryUnderstanding human pre-implantation development has important implications for assisted reproductive technology (ART) and for human embryonic stem cell (hESC)-based therapies. Owing to limited resources, the cellular and molecular mechanisms governing this early stage of human development are poorly understood. Nonetheless, recent advances in non-invasive imaging techniques and molecular and genomic technologies have helped to increase our understanding of this fascinating stage of human development. Here, we summarize what is currently known about human pre-implantation embryo development and highlight how further studies of human pre-implantation embryos can be used to improve ART and to fully harness the potential of hESCs for therapeutic goals. Key words: Human embryo, Oocyte to embryo transition, Zygote, Cleavage division, Blastocyst, Human embryonic stem cells, Aneuploidy IntroductionStudies of mammalian embryo development, especially in the mouse, have provided key insights into early mammalian developmental pathways. However, species-specific differences, for example in the timing of the major wave of genome activation, the patterns of gene expression, the frequency of chromosome missegregation and the patterns of epigenetic modifications, may limit the extrapolation of some findings to human embryo development. To date, studies of human pre-implantation development have utilized spare human pre-implantation embryos derived from in vitro fertilization (IVF; see Glossary, Box 1) to obtain insights into aspects of development specific to humans. Historically, these studies have focused on the morphological examination of embryos and the identification of factors that can improve in vitro culture, such as the conditions required to fertilize human oocytes in vitro, to cryopreserve and thaw human embryos and to promote human blastocyst formation. More recently, with the advent of advanced imaging techniques and sensitive gene expression profiling technologies, these studies are beginning to provide a clearer understanding of human pre-implantation development at cellular and molecular resolution. In addition, spare human pre-implantation embryos have enabled the derivation of human embryonic stem cells (hESCs), leading to the establishment of novel tools for human developmental biology and the emergence of a new field of research, namely hESC-based regenerative medicine. Thus, further investigations into the fundamental aspects of human pre-implantation development might provide not only insights into human developmental biology and common birth defects but also potential benefits for reproductive health and improvements in regenerative medicine.In this Primer, we delve further into the specifics of human preimplantation embryo development and discuss its relationship to that of other species. We also provide a summary of our current understanding of the molecular pathways of early human embryo development. Finally, we discuss how studies of hESCs can be used to further our understanding of early hum...

Early embryo mortality in natural human reproduction: What the data say

“…If Macklon’s (and Chard’s 19 ) estimates are excessive as the data suggest, this casts doubt on claims 113, 132 that the frequency of embryonic abnormalities observed in vitro is representative of the natural in vivo situation. In turn, this implies that many of the chromosomal abnormalities observed in in vitro human embryos are, to a greater extent than currently recognised 113 , an artefact of the clinical and experimental context of assisted reproduction technologies.…”

“…Furthermore, transferred embryos are selected based on quality criteria, however inexact those may be 111, 112 . IVF program manipulations may reduce π HCG compared to natural circumstances 3 and implantation failure remains a substantial issue for IVF 113, 114 . Although for IVF cycles, the reported live birth rate per cycle has gone up (from 14% in 1991 to 25.4% in 2012 34 ), comparison of IVF success rates and natural live birth fecundability values involves too many undefined variables to shed numerical light on early natural embryo development and mortality.…”

“…Widely held views on early embryo mortality may reflect an entrenched and biased view of the biology. For example, the Macklon “Black Box” review 20 has been cited over 200 times (Web of Knowledge citations on 10 th October 2016) with many articles explicitly referencing its 30% survival/70% failure value 8, 21, 113, 127– 133 . Macklon’s quantitative summary in his “Pregnancy Loss Iceberg” (30% implantation failure; 30% early pregnancy loss; 10% clinical miscarriage; 30% live births) is a direct, unedited reproduction of estimates published over 10 years previously 19 .…”

“…In turn, this implies that many of the chromosomal abnormalities observed in in vitro human embryos are, to a greater extent than currently recognised 113 , an artefact of the clinical and experimental context of assisted reproduction technologies.…”

DEsingle for detecting three types of differential expression in single-cell RNA-seq data

“…However, the GO terms enriched in DEs genes have no Table S1). E3 is around the 8-cell stage of preimplantation embryos (45), during which cell compaction occurs and functional gap junctions are formed (46,47). Cell compaction is initiated by the E-cadherin mediated cell adhesion (47)(48)(49)(50), and the genes related to cytoskeletal, cell junction and cell adhesion are also involved in this process (51).…”