TRANSLATIONAL BASIC SCIENCE & CLINICAL RESEARCH NEWS
The staff of The Reproductive Times here offers brief referenced notifications on interesting translational basic science & clinical research news with broad relevance to reproductive medicine and biology. Some of these news items may become subjects of more detailed reporting in The Reproductive Times on later occasions. The purpose of these relatively short notifications is to give readers the opportunity to get immediately more detailed information by looking up the listed references.
Importance of mechanical forces in early-stage embryos
European colleagues recently published an interesting paper on variability in mammalian embryogenesis which, of course, also relates to us humans.1 For the longest time molecular and cellular variability has been considered detrimental. More recently, however, it has become apparent that such variability plays a crucial role in cellular decision making and robustness. This makes the early variability in gene expression, cleavage timing, and in mechanical parameters in embryos an excellent model. In investigating embryos, they found that stochastic variability in cleavage timing played a very important role in achieving developmental consistency. Minimizing surface energy and compaction, moreover, select configurations with minimal energy needs and drive transitions in this direction, which leads to a decline in spatial variability. Finally, the zona pellucida apparently constrains the range of structures in early embryos. Combined robustness is ensured and these observations, moreover, demonstrate the potential adaptive benefit of stochastic processes in biological systems in general.
In a related paper in Nature magazine,2 using quail embryos as a model, French investigators demonstrated that mechanical forces that drive embryogenesis self-organize with contractility locally self-activating, followed by the resulting tension then acting as a long-range inhibitor, in this way shaping the embryo. The process also modulates gene expression which in turn facilitates emergence of specific embryonic territories. Like above-noted paper, this study also confirms the importance of mechanical forces for self-organization of embryos.
REFERENCES
1. Fabreges et al., Science 2024;386(6718):164
2. Caldarelli et al., Nature 2024;633:887-894
Early-stage imaging of the ovulating follicle and embryo
OVULATION IN THE MOUSE: A German team of investigators at the Max Plank Institute for Multidisciplinary sciences in Göttingen under the leadership of Prof. Dr. Melinda Schuh for the first time was able to observe and videotape ovulation of a follicle – in this case a mouse follicle.1,2 The authors demonstrated that ovulation proceeds through three distinct phases, namely: (i) follicle expansion, (ii) contraction, and (iii) rupture, which then results in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the explosive release of the egg.
A mouse egg is released from a follicle in real-time. (Image credit: Christopher Thomas, Tabea Lilian Marx et al. / Max Planck Institute for Multidisciplinary Sciences
GASTRULATION IN A HUMAN EMBRYO: And going from egg to embryo, researchers from the U.K and again Germany recently also reported the high resolution of single cell expression on a gastrulating human embryo.3 The study investigated a single donated human embryo staged at 16-19 days post-fertilization. The researchers then divided the single embryo into all of its single cells and sequenced the mRNA of 1195 individual cells making up the embryo, creating a very detailed map of gene expression at these crucial stages of embryo development. This study, thus, exceeded the 14-day rule of human embryo maintenance for experiments.
REFERENCES
1. Thomas et al., Nat cell Biol 2024;26:1997-2008
2. Cooke E. Live science October 29, 2024. https://www.livescience.com/health/fertility-pregnancy-birth/watch-1st-ever-video-of-ovulation-occurring-in-real-time
3. Qiu et al., Nature 2024;626:1084-1093
Metformin as an anti-aging agent
In a 40-month study of male monkeys, Chinese scientists documented significant anti-aging effects from metformin. Specifically, brain aging regressed by 6 years, and metformin protected brain structures, while enhancing cognitive abilities. The dosage the monkeys received was 20mg/kg.1 These data add to a significant amount of earlier data that suggests anti-aging benefits from metformin. Looking at metformin effects on ovarian aging would appear like a worthwhile research project.
REFERENCE
1. Yang et al. Cell 2024;187:6358-6378
A new ovarian benefit from DHEA
Another study by Chinese investigators revealed a new potential contribution by which DHEA may improve ovarian function: It appears that DHEA can promote vascular remodeling and, in the process, restore ovarian function in a rat model of cyclophosphamide-induced premature ovarian insufficiency. The potential recovery mechanism works through HIF-1a/VEGF signaling.
REFERENCE
1. Qin et al., Reprod Biomed Online 2024;49(3):10391
More on planned (social) oocyte cryopreservation
Israeli investigators offered in Human Reproduction Update a systematic review and meta-regression analysis. The findings are well summarized in the figure below: As the figure once again demonstrated return rates are extremely low (in this case 11%). Per woman live birth rates are somewhat low (28%) but have to be considered reasonable, especially if they are viewed age-adjusted.
What is the message? It appears increasingly clear that planned (social) egg-freezing is not a very economical way to extend fertility; but of course, it is better than nothing! And related, three prominent REs recently published an Insights in Women’s Health article in JAMA that adds to the subject,2 in which they reemphasize several generally well-known demographic facts: (i) Women are often unaware that success with fertility treatment declines with age. (ii) Misleading reports of children born to high-profile older women (usually the product of oocyte donation cycles) also do not help. (iii) Like in most of the developed world, the fertility rate in the US has declined from 70.9 births per 1000 women in 1990 to 56.1 per 1000 in 2022. At the same time, the age at first birth had risen from 27 years in 1990 to 30 years in 2019 as more women postponed first birth, all, of course, not very promising developments for the economic future of the country, short of increasing immigration.
REFERENCES
1. Hirsch et al., Hum Reprod Update 202; 30(5):558-568
2. Seifer et al., JAMA 2024. Doi:10.1001/jama.2024.18207