Blastomere size in the human 2-cell embryo predicts the division order that leads to imbalanced lineage contribution to the future body

Abstract

Retrospective tracing of somatic mutations predicted that most cells in the human body could be traced back to a single cell of the 2-cell stage embryo. Accordingly, a recent prospective study of the developmental trajectory of blastomeres in human embryos confirmed that progeny of the first 2-cell stage blastomere to divide generates more epiblast cells (future body). How the 2-cell blastomeres differ is unknown. Here, we show that 2-cell stage blastomeres in human embryos are asymmetric; they differ in size and the bigger blastomere divides first to 4-cell stage. We propose that this asymmetry might originate differences in cell fate.

Figure 1. Analysis of blastomere size and time of division in 2-cell human embryos

A. Schematic of the analysis used to generate data from human Embryoscope ^TM time-lapse movies. Two examples (single plane snapshots) from the movies are shown: before and after division of the bigger blastomere, pseudocolored in pink. The smaller blastomere is pseudocolored in blue. B. Quantification of the size difference between the two blastomeres of the 2-cell stage human embryo. Each datapoint represents the percentile difference between the two cells within individual 2-cell stage embryos. The centre line marks the median, the box contains the 25 ^th -75 ^th centile of the dataset, the whiskers mark the highest and lowest value, and the cross sign marks the mean. C. Quantification of order of division of blastomeres in 2-cell human embryos in relation to their size. Student’s t-test, p = 0.0000096 (****). n = 83 embryos. D . Scatter plot showing the correlation between % size difference (bigger/smaller) of the blastomeres of two-cell stage human embryos vs difference in time of their division (in hours, time of smaller blastomere division – time of bigger blastomere division). R = 0.04, p = 0.71.