Author(s): Meiling Zhang, Fanghao Guo, Qing Zhang, Qianhui Hu, Di Sun, Yongjian Ma, Yanquan Li, Mengxi Guo, Haixia Ding, Ying Guo, Baichai Yang, Songmao Li, Ningxia Sun, Yuxuan Zheng, Wen Li

Description: Ovarian aging is a complex process that compromises fertility and elevates the risk of reproductive disorders. To elucidate its spatiotemporal dynamics, we integrated single-nucleus RNA sequencing and spatial transcriptomics to construct a... Ovarian aging is a complex process that compromises fertility and elevates the risk of reproductive disorders. To elucidate its spatiotemporal dynamics, we integrated single-nucleus RNA sequencing and spatial transcriptomics to construct a comprehensive aging atlas of 12 human ovarian tissues spanning ages 12–54 (prepubertal, age 12, n = 1; young, ages 23–29, n = 4; middle-aged, ages 32–34, n = 2; and older-aged, ages 42–54, n = 5). Our analysis revealed aging-related transcriptomic shifts, including impaired mitochondrial oxidative phosphorylation and reproductive structure development in aged human ovaries. We identified a novel endothelial cell (EDC) subtype, CLDN5+ blood EDCs, which exhibited unique functional specialization as semiprofessional antigen-presenting cells. In contrast to other cell types that lost cell identity during aging, CLDN5+ blood EDCs displayed transcriptomic sensitivity to aging, characterized by enhanced antigen-presenting capabilities, and heightened inflammatory activity. Spatial mapping further uncovered immunoglobulin-expressing (IGHG1+/IGKC+) cell accumulation in the ovarian periphery, correlating with advancing age. Critically, aging disrupted global cellular connectivity while amplifying the DLK1:NOTCH3 axis between theca cells and CLDN5+ blood EDCs, which may contribute to the dysregulation of ovarian functions. We also detected the upregulation of DLK1 in granulosa cells from patients with primary ovarian insufficiency. This study significantly enhances our comprehension of the underlying mechanisms of human ovarian aging and concurrently pinpoints potential therapeutic avenues for addressing related disorders. [Show details]

Author(s): Meiling Zhang, Di Liu, Songmao Li, Jiansheng Liu, Fanghao Guo, Haibin Zhu, Li Zhang, Di Sun, Yu Yan, Yanquan Li, Rui Qiao, Haixia Ding, Qing Zhang, Mengxi Guo, Yongjian Ma, Zhiwei Liu, Wen Li, Yuxuan Zheng

Description: SARS-CoV-2 infection has raised significant concerns regarding its impact on assisted reproductive technology. We found that oocyte retrieval during acute SARS-CoV-2 infection significantly reduced the rates of good-quality blastocyst... SARS-CoV-2 infection has raised significant concerns regarding its impact on assisted reproductive technology. We found that oocyte retrieval during acute SARS-CoV-2 infection significantly reduced the rates of good-quality blastocyst formation, but the underlying molecular mechanisms remain poorly understood. To address this, we investigated the effects of maternal acute SARS-CoV-2 infection on preimplantation embryo development and the early offspring hematopoietic system. Using single-cell RNA sequencing (scRNA-seq), we identified developmental delays in morphologically normal blastocysts from infected mothers, characterized by prolonged expression of zygotic genome activation-related genes, downregulation of mTORC1 signaling, and altered energy metabolism, including suppressed oxidative phosphorylation (OXPHOS) and enhanced glycolysis. We further revealed that maternal acute infection induced abnormal methylation/demethylation patterns in preimplantation embryos. To assess the potential long-term impact on offspring, we conducted integrated multi-tissue analyses, including bulk RNA-seq and genome-wide DNA methylation profiling of placental tissues, along with scRNA-seq of umbilical cord blood (UCB) cells from neonates delivered by SARS-CoV-2-infected mothers. Neonates exhibited elevated levels of inflammatory cytokines and an increased abundance of monocytes, indicating an activated myelopoiesis response. In addition, hematopoietic stem and progenitor cells (HSPCs) from UCB showed reduced OXPHOS activity and a skewed differentiation bias toward the myeloid lineage, potentially impacting long-term immune function. Collectively, these findings reveal that maternal acute SARS-CoV-2 infection impairs preimplantation embryo development and leaves a lasting imprint on offspring hematopoietic health through dysregulated energy metabolism, epigenetic modifications, and altered immune responses. [Show details]