bims-reprim 2021-01-03 papers

Issue of 2021‒01‒03
four papers selected by
Iva Filipovic
Karolinska Institutet

Nature. 2020 Dec 23.

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

DOI: https://doi.org/10.1038/s41586-020-03071-0

Biol Reprod. 2020 Dec 22. pii: ioaa232. [Epub ahead of print]

Developmental programming of the female reproductive system-a review.

Sijia Yao, Jorge Lopez-Tello, Amanda N Sferruzzi-Perri.

Exposures to adverse conditions in utero can lead to permanent changes in the structure and function of key physiological systems in the developing fetus, increasing the risk of disease and premature aging in later postnatal life. When considering the systems that could be affected by an adverse gestational environment, the reproductive system of developing female offspring may be particularly important, as changes have the potential to alter both reproductive capacity of the first generation, as well as health of the second generation through changes in the oocyte. The aim of this review is to examine the impact of different adverse intrauterine conditions on the reproductive system of the female offspring. It focuses on the effects of exposure to maternal undernutrition, overnutrition/obesity, hypoxia, smoking, steroid excess, endocrine disrupting chemicals and pollutants during gestation and draws on data from human and animal studies to illuminate underlying mechanisms. The available data indeed indicate that adverse gestational environments alter the reproductive physiology of female offspring with consequences for future reproductive capacity. These alterations are mediated via programmed changes in the hypothalamic-pituitary gonadal axis and the structure and function of reproductive tissues, particularly the ovaries. Reproductive programming may be observed as a change in the timing of puberty onset and menopause/reproductive decline, altered menstrual/estrous cycles, polycystic ovaries and elevated risk of reproductive tissue cancers. These reproductive outcomes can affect the fertility and fecundity of the female offspring, however, further work is needed to better define the possible impact of these programmed changes on subsequent generations.

Keywords: DOHAD; HPG; Programming; fertility; fetal; offspring; ovary; reproduction

DOI: https://doi.org/10.1093/biolre/ioaa232

Front Pediatr. 2020 ;8 605219

Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation.

Mira N Moufarrej, Ronald J Wong, Gary M Shaw, David K Stevenson, Stephen R Quake.

In recent years, there have been major advances in the application of non-invasive techniques to predict pregnancy-related complications, for example by measuring cell-free RNA (cfRNA) in maternal blood. In contrast to cell-free DNA (cfDNA), which is already in clinical use to diagnose fetal aneuploidy, circulating RNA levels can correspond with tissue-specific gene expression and provide a snapshot of prenatal health across gestation. Here, we review the physiologic origins of cfRNA and its novel applications and corresponding challenges to monitor fetal and maternal health and predict pregnancy-related complications.

Keywords: IUGR; cell-free RNA; prediction; preeclampsia; preterm birth; transcriptome

DOI: https://doi.org/10.3389/fped.2020.605219

STAR Protoc. 2020 Dec 18. 1(3): 100134

A Protocol for Evaluating Vital Signs and Maternal-Fetal Parameters Using High-Resolution Ultrasound in Pregnant Mice.

Jose Galaz, Roberto Romero, Marcia Arenas-Hernandez, Bogdan Panaitescu, Valeria Garcia-Flores, Nardhy Gomez-Lopez.

Pregnancy is a unique physiological state in which two individuals coexist: the mother and the fetus. Disruption of maternal-fetal crosstalk leads to pregnancy and neonatal pathologies. Therefore, assessing maternal-fetal well-being is essential for understanding the physiological and pathological processes occurring during pregnancy. Herein, we provide a protocol that allows for the determination of body temperature, blood pressure, and the evaluation of uterine and umbilical arteries as well as maternal and fetal heart rate using high-resolution ultrasound in pregnant mice. For complete details on the use and execution of this protocol, please refer to Gomez-Lopez et al. (2020).

DOI: https://doi.org/10.1016/j.xpro.2020.100134