Developmental capacity is unevenly distributed among single blastomeres of 2-cell and 4-cell stage mouse embryos

Abstract

During preimplantation development, mammalian embryo cells (blastomeres) cleave, gradually losing their potencies and differentiating into three primary cell lineages: epiblast (EPI), trophectoderm (TE), and primitive endoderm (PE). The exact moment at which cells begin to vary in their potency for multilineage differentiation still remains unknown. We sought to answer the question of whether single cells isolated from 2- and 4-cell embryos differ in their ability to generate the progenitors and cells of blastocyst lineages. We revealed that twins were often able to develop into blastocysts containing inner cell masses (ICMs) with PE and EPI cells. Despite their capacity to create a blastocyst, the twins differed in their ability to produce EPI, PE, and TE cell lineages. In contrast, quadruplets rarely formed normal blastocysts, but instead developed into blastocysts with ICMs composed of only one cell lineage or completely devoid of an ICM altogether. We also showed that quadruplets have unequal capacities to differentiate into TE, PE, and EPI lineages. These findings could explain the difficulty of creating monozygotic twins and quadruplets from 2- and 4-cell stage mouse embryos.

Blastomeres of 8-cell mouse embryos differ in their ability to generate embryonic stem cells and produce lines with different transcriptional signatures

“…Several studies have shown that blastomeres isolated from most precompaction embryos differ in their ability to form TE, EPI, and PE cells, indicating their unequal developmental potential ( Krawczyk et al, 2021 ; Maemura et al, 2021 ). A developmental bias among sister blastomeres has also been reported in intact 4-cell and 8-cell mouse embryos, in which lineage tracing experiments demonstrated that most individual embryos contain blastomeres exhibiting biased and unbiased contribution patterns to TE and ICM and their derivatives ( Tabansky et al, 2013 ).…”

“…In addition to this biological constraint, the plasticity of embryonic development and the presence of signaling modulators in the derivation medium should also be considered when interpreting the results of our study. Blastomeres of 8-cell embryos show impaired ability to form pluripotent EPI cells after isolation and culture in standard embryo culture medium, and they tend to develop as trophoblastic vesicles instead of forming blastocysts ( Krawczyk et al, 2021 ; Maemura et al, 2021 ). This could be attributed to the lack of cell-cell contacts and positional information, which was shown to induce blastomeres to change their gene expression pattern towards a unique pattern characteristic of neither ICM nor TE, but with a tendency to mimic that of TE cells ( Lorthongpanich et al, 2012 ).…”

“…It is still unclear at what developmental stage embryonic cells start to differ in their potential to differentiate into these multiple lineages, but mounting evidence suggests that a developmental bias may already be present in early cleavage-stage blastomeres. In this sense, recent studies have shown that sister blastomeres of 2-cell and 4-cell mouse embryos have unequal capacities to form EPI, PE and TE lineages ( Casser et al, 2017 ; Krawczyk et al, 2021 ; Maemura et al, 2021 ). Multicolor lineage tracing has also revealed that sister blastomeres of intact 4-cell embryos display a bias in contributing to either TE or ICM ( Tabansky et al, 2013 ).…”

Omics Views of Mechanisms for Cell Fate Determination in Early Mammalian Development

“…As the development of early embryos is punctual and regular, what mechanisms drive the switching between different lineage patterns and adjust the mismatch between the position and fate of a certain cell? In view of the powerful cell totipotency and embryonic plasticity in mouse 2- and 4-cell embryos [96] , [97] , [98] , whether the molecular asymmetry can be inherited or reconstructed in new 2- and 4-cell embryos developed from “half”- and “one-quarter”-cleaving embryos is an exciting scientific question waiting to be explored. The answers to these questions will provide a clear view of the detailed mechanisms for early cell fate regulation.…”

First cleavage is a manifestation of the geometry of the unfertilized oocyte: implications for monozygotic twinning in mice

“…Each dissociated blastomere would develop into a pluteus larva, albeit not always of the same size, and this behavior seemed to relate to how the plane of 1 st cleavage was oriented. From 2017 onwards, increasing evidence has been showing that when mouse blastomeres are separated at the 2-cell stage, only one blastomere is able to develop into a viable blastocyst or develop fully into a live mouse in most cases (Casser et al ., 2017; Krawczyk et al ., 2021; Maemura et al ., 2021). Full developmental potential is probably attained when the blastomere progeny accrues sufficient epiblast cells by the blastocyst stage (Morris et al ., 2012).…”