INSIGHT of Medicine(phase 14,2024)

1.Loss-of-function mutations in CEP78 cause male infertility in humans and mice

DOI: 10.1126/sciadv.abn0968

https://www.science.org/doi/10.1126/sciadv.abn0968

The passage describes the role of centrosomal proteins in male infertility and the identification of a splicing mutation in the CEP78 gene in infertile patients. These patients exhibited reduced sperm count and motility, as well as abnormal sperm morphology. The researchers also created Cep78 knockout mice, which exhibited similar reproductive abnormalities. Intracytoplasmic sperm injection treatment did not rescue the infertility in both patients and mice. The study suggests that CEP78 regulates the expression of USP16, which then stabilizes Tektin levels through ubiquitination. Additionally, the knockout mice showed impairments in the retina and outer hair cells in the cochlea, indicating a broader role for CEP78 in these functions. Overall, nonfunctional CEP78 is identified as a critical factor in male infertility and has implications for retinal and hair cell function in mice.

2.Primary specification of blastocyst trophectoderm by scRNA-seq: New insights into embryo implantation

DOI: 10.1126/sciadv.abj3725

https://www.science.org/doi/10.1126/sciadv.abj3725

The passage points out the lack of understanding regarding the mechanisms of implantation and the causes of implantation failure. To investigate these processes, the researchers conducted single-cell RNA sequencing on peri-implantation embryos from humans and mice. They discovered that the transcriptomes of polar and mural trophectoderm (TE) diverged after embryo hatching, with polar TE being more mature than mural TE in both species. The implantation poles exhibited similarities in cell cycle activities and gene expression related to implantation and placentation. Abnormalities in energy production, protein metabolism, and RNA methylation were observed in embryos that failed to attach in vitro or implant in vivo. These findings provide new insights into the gene expression characteristics and differentiation of TE during the peri-implantation period in humans and mice and contribute to our understanding of embryo implantation.

3.Rescuing lung development through embryonic inhibition of histone acetylation

DOI: 10.1126/scitranslmed.adc8930

https://www.science.org/doi/10.1126/scitranslmed.adc8930

The passage discusses the challenges faced in utilizing genomic diagnosis for patients with congenital malformations and the lack of knowledge about how specific genetic variants contribute to disease development. It focuses on congenital diaphragmatic hernia (CDH), a severe structural malformation, and the unclear underlying mechanisms. The researchers identified genetic variants in the SIN3A gene in two CDH patients. Deleting Sin3a specifically in mouse tissues resulted in defects in diaphragm development, lung hypoplasia, and pulmonary hypertension, which are major characteristics of CDH and contribute to associated mortality. Loss of SIN3A in lung tissue led to reduced cellular differentiation, impaired cell proliferation, and increased DNA damage. Treatment of embryonic Sin3a mutant mice with anacardic acid, an inhibitor of histone acetyltransferase, showed positive effects such as reduced DNA damage, increased cell proliferation and differentiation, improved lung and pulmonary vascular development, and reduced pulmonary hypertension. These findings suggest that restoring the balance of histone acetylation can improve lung development in a mouse model of CDH associated with SIN3A mutations.

4.Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary

DOI: 10.1126/sciadv.abn4564

https://www.science.org/doi/10.1126/sciadv.abn4564

The article focus on es the problem of irregular and disordered release of oocytes with aging and obesity, leading to fertility loss in females. The researchers identify fibrosis in the ovarian stromal compartment as a key mechanism underlying impaired oocyte release. This fibrosis is initiated by mitochondrial dysfunction, which leads to reduced bioenergetics, oxidative damage, inflammation, and collagen deposition. The study demonstrates that two antifibrosis drugs, pirfenidone and BGP-15, can eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice. This restoration is associated with changes in macrophage polarization and an increase in the MMP13 protease. These findings provide evidence that ovarian fibrosis can be reversed, suggesting that drugs targeting mitochondrial metabolism could be a potential therapeutic strategy for women with metabolic disorders or advancing age to help maintain ovarian function and extend fertility.

5.Modeling embryo-endometrial interface recapitulating human embryo implantation

DOI: 10.1126/sciadv.adi4819

https://www.science.org/doi/10.1126/sciadv.adi4819

The initiation of human pregnancy is marked by the implantation of an embryo into the uterine environment; however, the underlying mechanisms remain largely elusive. To address this knowledge gap, the scientists developed hormone-responsive endometrial organoids (EMO), termed apical-out (AO)–EMO, which emulate the in vivo architecture of endometrial tissue. The AO-EMO comprise an exposed apical epithelium surface, dense stromal cells, and a self-formed endothelial network. When cocultured with human embryonic stem cell–derived blastoids, the three-dimensional feto-maternal assembloid system recapitulates critical implantation stages, including apposition, adhesion, and invasion. Endometrial epithelial cells were subsequently disrupted by syncytial cells, which invade and fuse with endometrial stromal cells. The article provides a foundation for investigating embryo implantation and feto-maternal interactions, offering valuable insights for advancing reproductive medicine.