Hypoxic mesenchymal stem cell-derived exosomal circDennd2a regulates granulosa cell glycolysis by interacting with LDHA

作者：Wenxin Li, Minjun Lu, Junyu Shang, Jiamin Zhou, Li Lin, Yueqin Liu, Dan Zhao, Xiaolan Zhu · 发表于：Stem Cell Research & Therapy · 年份：2024 · DOI：10.1186/s13287-024-04098-0 · 被引用次数：10 · 研究领域：Reproductive Biology and Fertility、Extracellular vesicles in disease、Sperm and Testicular Function

BACKGROUND: Premature ovarian insufficiency (POI) is an ovarian dysfunction disorder that significantly impacts female fertility. Ovarian granulosa cells (GCs) are crucial somatic components supporting oocyte development that rely on glycolysis for energy production, which is essential for follicular growth. Hypoxia-induced exosomal circRNAs regulate glycolysis, but their biological functions and molecular mechanisms in POI are largely unexplored. The present comprehensive investigation revealed a substantial reduction in ovarian glycolysis levels in POI rats. Notably, hypoxia-induced exosomes originating from mesenchymal stem cells (HM-Exs) exhibit a remarkable capacity to enhance ovarian glycolysis, mitigate GCs apoptosis, reinstate disrupted estrous cycles, modulate sex hormone levels, and curtail the presence of atretic follicles. These restorative actions collectively contribute to fostering fertility revival in POI-afflicted rats. METHODS: Cyclophosphamide was administered for 2 weeks to induce POI rat model, and POI rats were randomly divided into three groups and treated with PBS, NM-Exs and HM-Exs, respectively. Ovarian function and fertility were assessed at the end of the study and ovarian tissues were collected for analysis of energy metabolites. The relationship between circDennd2a and POI was explored in vitro by qRT-PCR, Western blotting, CCK-8 assay, EdU staining, TUNEL staining, extracellular acidification rate (ECAR) measurements, and ATP, lactate and pyruva...