Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period

The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. Researchers at the Igenomix Foundation aimed to investigate the potential for vertical DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. The researchers discovered that the human endometrium secretes all three general subtypes of EV – apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) – into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of mitochondrial (mt)DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, the researchers demonstrate the internalization of EV-derived nuclear-encoded (n)DNA/mtDNA by trophoblast cells of murine embryos, which associates with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that nDNA/mtDNA become packaged into secreted EVs that the embryo uptakes, and that the transfer of DNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.

Internalization of endometrial extracellular vesicle-derived
DNA by cells of the murine embryo.

Confocal images show hatched embryos after co-culture with EdU-tagged ABs, MVs, and EXOs isolated from Ishikawa cell supernatants. Embryo membranes were visualized with Wheat germ agglutinin (WGA) in red, embryo nuclei with DAPI, and EdU-tagged transferred DNA in green. Zoomed images taken from the areas demarcated by white boxes in merge images. Cell-free DNA and residual small-sized EVs were used as control conditions (Neg). Scale bar in zoom = 20 µm.

Bolumar D, Moncayo-Arlandi J, Gonzalez-Fernandez J, Ochando A, Moreno I, Monteagudo-Sanchez A, Marin C, Diez A, Fabra P, Checa MA, Espinos JJ, Gardner DK, Simon C, Vilella F. (2023) Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period. Elife Dec 27;12:RP88008.[article]

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