REVIEWS AND COMMENTARY on recent literature in reproductive medicine and biology
The staff of THE REPRODUCTIVE TIMES here offers commentaries on recently published articles, primarily chosen for educational values – in the positive but also in the negative –, for clinical purposes, and for their potential translational values to clinical medicine when addressing basic science in reproductive medicine and biology.
Lineage segregation in the mammalian preimplantation-stage embryo
The subject of lineage segregation in preimplantation stage embryos has been very well elucidated over the last decade in basic science journals but has found little attention in more clinical journals in the field. A review article updating the subject in Human Reproduction can, therefore, be viewed as timely, even though it does not contribute new information for the already educated reader (1).
Unfortunately, the article completely omits a discussion of the differences between embryonic and extraembryonic cell lineages in their respective abilities to self-correct from aneuploid cells. Since this is a subject of still considerable controversy and is a very important issue in the still raging discussion about the clinical utilization of preimplantation genetic testing for aneuploidy (PGT-A), this is an almost inexcusable shortcoming, which characterizes this article as a bit too superficial for basic scientists and devoid of what likely is the most important relevance of the addressed subject for clinicians.
Reference
1. Skory RM. Hum Reprod 2024;39(9):1889-1898
At least in the mouse, embryonic genome instability may happen in waves
We are delighted to present another interesting paper by Japanese colleagues regarding preimplantation-stage embryos. At least in a mouse model, they recently demonstrated in a paper published in Nature magazine that at 1- and 2-cell stage embryos lacked a replication timing program for DNA, with the complete genome replicating slowly through slow-moving replication forks. Such a program, however, started abruptly somatic-cell-like, though with still slow fork speed, extended S phase, and appearance of markers of replication stress, DNA damage as well as repair. Especially during the 4- to 8-cell division breakpoints it became enriched in late replication regions, with errors rescued by nucleoside supplementation, which accelerated fork speed and reduced replication stress. By 8-cell stage, forks had gained speed, S-phase was of normal length, and chromosome aberrations decreased again (1). Why another Japanese study that was just recently published demonstrated the process to be more gradual (2), remained unexplained.
References
1. Takahashi et al., Nature 2024;633:686-694
2. Nakatani et al., Nature 2024; 625:401-404
Rejuvenating aged oocytes through exposure to a young follicular microenvironment?
It is these days, unfortunately, quite popular for many IVF clinic to advertise ovarian “rejuvenation” procedures. What is referred to in most cases is the injection of platelet-rich plasma (PRP) into ovaries, something we would not call a rejuvenation process, but that to a degree is semantics. But now come Chinese investigators who claim to have really found the “fountain of youth” – at least in a mouse model – in a very simple experiment (1). They took “old” eggs from follicles of older females and, basically, exchanged the follicles for follicles from younger females. In other words, they gave older eggs the environmental support of younger eggs and – lo and behold – those older eggs were significantly improved in maturation rates, blastocyst formation, and live births after IVF. Moreover, this rejuvenation was also associated with enhanced interaction with somatic cells, transcriptomic and metabolomic remodeling, improved mitochondrial function, and higher fidelity of meiotic chromosome segregation. A switch to the opposite direction – placing younger oocytes into older follicles – had the opposite effects.
If confirmed – and especially if confirmed in humans – this, as the authors note, opens the door for future somatic follicular cell-based therapy for age-based female infertility, but there is more to these results if confirmed: likely the most important conclusion then would be that oocytes at resting stage do not age after all. This was before suggested, mostly based on the fact that primordial follicles before recruitment show almost no metabolic activity. The suggestion made then was similar to what here reviewed paper suggests, namely that what ages as women get older is the somatic microenvironments in the ovary in which follicles mature following recruitment out of resting stage in primordial follicles. If confirmed, indeed, very exciting finding that may really allow for true rejuvenation of ovarian function in older women if this microenvironment can be improved.
Reference
1. Wang et al., Nat Aging 2024;4:1194-1210
Human stem cells in regenerative medicine
Related to the previous subject, a Review of the increasing use of human stem cells in regenerative medicine affecting many different medical specialties was recently addressed in the American Journal of Medicine (1). The authors in this article noted that, “medicine now has the potential of improving many human diseases by introducing adult somatic stem cells that can repair and/or replace defective or damaged tissue.” Though we feel that this statement is an exaggeration of current capabilities, it was to a degree mitigated by the authors by also noting that these treatments are still “in an early phase of development” and, therefore, must be introduced into clinical practice with maximal safety and only after proper validation.
This, however, is unfortunately, not what is happening in many medical fields, reproductive medicine included. Adult stem cells are already injected into ovaries, without – to the best of our knowledge – any safety studies in animal models ever performed. The ovaries are a highly cancerogenous organ and, therefore, must be treated with great caution. We, therefore, as of this moment, would caution women against allowing stem cell injections into their ovaries.
Reference
1. Goetzl et al., Am J Med 2024;137:805-809