Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.
Read more about eLife’s peer review process.Editors
- Reviewing EditorJun WuThe University of Texas Southwestern Medical Center, Dallas, United States of America
- Senior EditorWei YanWashington State University, Pullman, United States of America
Reviewer #1 (Public Review):
Bolumar et al. isolated and characterized EV subpopulations, apoptotic bodies (AB), Microvesicles (MV), and Exosomes (EXO), from endometrial fluid through the female menstrual cycle. By performing DNA sequencing, they found the MVs contain more specific DNA sequences than other EVs, and specifically, more mtDNA were encapsulated in MVs. They also found a reduction of mtDNA content in the human endometrium at the receptive and post-receptive period that is associated with an increase in mitophagy activity in the cells, and a higher mtDNA content in the secreted MVs was found at the same time. Last, they demonstrated that the endometrial Ishikawa cell-derived EVs could be taken by the mouse embryos and resulted in altered embryo metabolism.
This is a very interesting study and is the first one demonstrating the direct transmission of maternal mtDNA to embryos through EVs.
Reviewer #2 (Public Review):
In Bolumar, Moncayo-Arlandi et al. the authors explore whether endometrium-derived extracellular vesicles contribute mtDNA to embryos and therefore influence embryo metabolism and respiration. The manuscript combines techniques for isolating different populations of extracellular vesicles, DNA sequencing, embryo culture, and respiration assays performed on human endometrial samples and mouse embryos.
Vesicle isolation is technically difficult and therefore collection from human samples is commendable. Also, the influence of maternally derived mtDNA on the bioenergetics of embryos is unknown and therefore novel. However, several experiments presented in the manuscript fail to reach statistical significance, likely due to the small sample sizes. Additionally, the experiments do not demonstrate a direct effect of mtDNA transfer on embryo bioenergetics. This has the unfortunate consequence of making several of the authors' conclusions speculative.
In my opinion the manuscript supports the following of the authors' claims:
1. Different amounts of mtDNA are shed in human endometrial extracellular vesicles during different phases of the menstrual cycle.
2. Endometrial microvesicles are more enriched for mitochondrial DNA sequences compared to other types of microvesicles present in the human samples.
3. Fluorescently labelled DNA from extracellular vesicles derived from an endometrial adenocarcinoma cell line can be incorporated into hatched mouse embryos.
4. Culture of mouse embryos with endometrial extracellular vesicles can influence embryo respiration and the effect is greater when cultured with isolated exosomes compared to other isolated microvesicles.
My main concerns with the manuscript:
1. The authors demonstrate that microvesicles contain the most mtDNA, however, they also demonstrate that only isolated exosomes influence embryo respiration. These are two separate populations of extracellular vesicles.
2. mtDNA is not specifically identified as being taken up by embryos only DNA.
3. The authors do not rule out that other components packaged in extracellular vesicles could be the factors influencing embryo metabolism.
Taken together, these concerns seem to contradict the implication of the title of the manuscript - the authors do not demonstrate that inheritance of maternal mtDNA has a direct causative effect on embryo metabolism.
