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

Author:

Bolumar David1ORCID,Moncayo-Arlandi Javier2,Gonzalez-Fernandez Javier2,Ochando Ana2,Moreno Inmaculada2,Monteagudo-Sanchez Ana2,Marin Carlos1,Diez Antonio1,Fabra Paula3,Checa Miguel Angel34,Espinos Juan Jose35,Gardner David K67ORCID,Simon Carlos289,Vilella Felipe2ORCID

Affiliation:

1. Igenomix Foundation, INCLIVA Health Research Institute

2. Carlos Simon Foundation, INCLIVA Health Research Institute

3. Clinica Fertty

4. Department of Medicine and Life Sciences, University Pompeu Fabra

5. Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, UAB

6. School of Biosciences, University of Melbourne

7. Melbourne IVF

8. Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia

9. Department of Obstetrics and Gynecology, BIDMC, Harvard University

Abstract

The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We 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. We 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, we 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.

Funder

Instituto de Salud Carlos III

Ministerio de Educación, Cultura y Deporte

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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