A study by the IVI Foundation entitled Hsa-miR-30-d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome, published in Development scientific journal by IVI researchers Felipe Vilella and Carlos Simón – Scientific Director of FIVI – has shown, for the first time, an early extension of the Barker theory postulated in 1990 suggesting that “what happens in the maternal uterus is more important that what happens at home after the birth”:
This study demonstrates that the future mother through molecules secreted in her uterus can modify the genetic information of the future child. This finding can be extensive when the ovum is from a donor or between an expectant surrogate mother and the embryo of the biological mother, which completely changes the paradigm of egg donation and surrogacy. It opens the door for the genetic input of mothers who have to rely oocyte donation in order to fulfil their desire to have children and alerts those who must use surrogacy for medical reasons due to the importance of the surrogate mother for their genetic offspring.
“These findings show us that there is an exchange between the endometrium and the embryo, which is something that we already suspected as a result of the coincidence of certain physical characteristics between mothers and children born through egg donation and also due to the incidence of diseases in children related to maternal pathologies during pregnancy, such as obesity or cigarrete smoking”, explained researcher Felipe Vilella.
Certain conditions to which women are exposed end up modifying their cells (including those of the endometrium): smoking and obesity both do this. This in turn causes changes to the endometrial fluid and its secretion; genetic information from the pregnant woman is released, which is taken up by the embryo, thus modifying its development.
“This communication may cause specific functions to be expressed or inhibited in the embryo,” explained the researchers. “As such, this publication opens up the possibility to understand this maternal “epigenetic” regulation. Knowing that this transmission exists, in the future we will be able to detect how to interrupt it, putting an end to the trend of obese mothers, obese children. In countries where surrogacy is permitted we will be able to attribute more importance to the history of the pregnant woman’s habits prior to pregnancy.”
Source – https://www.ivi-fertility.com/
Schematic of a novel maternal-fetal cross-talk mechanism promoted by hsa-miR-30d. Hsa-miR-30d is delivered to the EF from the maternal endometrium, modifying the embryo transcriptome and its adhesive phenotype.
After reading this blog I present this paper in my journal club. We find multiple big mistakes that has been corroborated by others in pubpeer.
on Figure 2, the text suggests that “Western blot analysis showed that the exosome fraction from primary human endometrial epithelial cell (hEEC) culture was positive for the three exosomal tetraspanins CD63, CD81 and CD9…”. Looking at Figure 2D, the first lane (presumably a whole cell sample) shows a weak CD63 band but it’s not discernible (to me) in any of the supernatant or exosome fractions from the 3 biopsies (unlike the CD81 and CD9 bands). Doesn’t this argue against CD63 being in the exosomes and thus being a good marker?
The group then go on to utilise SmartFlares to assess the location of miRNA. We’ve been running a project looking at SmartFlares and in our hands, they do not report on RNA levels, but remain trapped in the endosomes into which they were internalised. The fluorescence that is seen is likely the effect of nucleases in the endocytic pathway which cleave the RNA and de-quench the fluorophore. For more details see [http://bit.ly/1MmiTrR] and [http://bit.ly/1LWXWBH].
Putting aside the fluorescent data (with their amusingly-huge but probably-erroneous 3mm scale bars), the group reports the presence of gold nanoparticles in vesicles. Given that SmartFlares are originally taken up into endosomes, this should not be surprising at all, and certainly should not be taken as evidence at the target miRNA is also in endosomes! If this is your interpretation then what you’re suggesting is that:
– SmartFlares are internalised by endocytosis
– SmartFlares escape endosomes (there’s no evidence for this)
– SmartFlares interact with miRNA displacing the fluorophore
– SmartFlare core/miRNA complex gets taken up again into vesicles
(- SmartFlare core/miRNA is expelled from the cell as exosomes)
I infer the last one as SmartFlare gold-core containing purified exosomes are not shown in the paper, although from a reviewer’s perspective, this seems like an important experiment. Regardless, this chain of events is a long way from Occam’s Razor.
Moving on, in Figure 5 there seems to be a big misunderstanding about how SmartFlares work. Here a layer of hEECs are labelled with miR-30d SmartFlares, then an unlabelled embryo is introduced to the culture (replicating implantation). The authors state that “The miR-30d signal was observed to transfer from the hEECs to the trophectoderm of embryos when they were attached to the hEEC monolayer.” Even if the SmartFlares are working as advertised, it is the gold core that would be labelling the miRNA, not the Cy3.
In figure 2:
What is identified as “an endosome proximal to the plasma membrane with a small exosome (arrow)”
it is just a common EM artefact. You can easily follow the exosome membrane to see clearly that is a rolling artefact due to the sample preparation. The cracking point is easily identified in the endosome membrane just unroll and follow.
In the same panel, it is also amazing the reviewers and editors allow publishing a blur image, it is the first time that I have seen this in Dev.
Discussion is interesting: As far as I have understand they show that a miRNA in mouse embryos increase adhesion in human epithelium. Why the discussion starts like this:
“The ‘Barker hypothesis’ suggests that “the womb may be more important than the home”, emphasizing the concept that the maternal endometrium has a reprogramming effect on the embryo, fetus and adult (Barker, 1990, 1997). To date, no strong evidence has implicated molecules secreted in the EF in the origin of adult diseases. However, accumulated evidence suggests that intrauterine exposure of fetuses in patients with diabetes or obesity confers an increased risk of these diseases in the adult life of offspring (Clausen et al., 2008).”
I cannot see any relationship between this work and this issue, at least to start the discussion- yes, here are miRNAs but reprogramming is far to claim with thoos data.
Can anyone see any peer-rev work here? In my modest opinion editor would have to blush in shame.