Human urine stem cells protect against cyclophosphamide-induced premature ovarian failure by inhibiting SLC1A4-mediated outflux of intracellular serine in ovarian granulosa cells

作者：Hao‐Cheng Gu, Lingfang Wang, Yuwei Zhang, Youqiong Zhuo, Zhou-Hang Zhang, Xie Wei, Quanwen Liu, Ke‐Yu Deng, Hong‐Bo Xin · 发表于：Cellular & Molecular Biology Letters · 年份：2025 · DOI：10.1186/s11658-025-00701-1 · 被引用次数：13 · 研究领域：Reproductive Biology and Fertility、Extracellular vesicles in disease、Ovarian cancer diagnosis and treatment

BACKGROUND: Cyclophosphamide (CTX) is the first-line medication for the treatment of breast cancer, although it potentially leads to severe ovarian dysfunction and even premature ovarian failure (POF). However, the mechanism of CTX-induced POF remains unclear. Mesenchymal stem cell-based therapy has been wildly used for treating numerous diseases. Therefore, our study aims to elucidate the underlying mechanism of CTX-induced POF and to explore the therapeutic effect of human urine stem cells (hUSCs) in POF. METHODS: CTX-induced POF or ovarian granulosa cell (GCs) apoptosis were treated with hUSCs and their exosomes in vitro and in vivo. Morphological, histological, and functional alternations were examined using multiple approaches. The effector molecules of hUSC-derived exosomes (hUSC-Exo) were determined by differential expression analysis in the ovaries. The target genes of miRNA were accessed by transcriptome sequencing in GCs, and the underlying mechanisms were further elucidated. RESULTS: hUSCs remarkably inhibited CTX-induced apoptosis and promoted the proliferation of GCs, respectively. In addition, we observed that miR-27b-3p was highly expressed in hUSC-Exo and markedly suppressed CTX-induced GC apoptosis by specifically inhibiting the expression of SLC1A4, a serine transporter, in ovarian GCs, which, in turn, elevated the concentration of the intracellular serine by inhibiting the outflux of cellular serine. More importantly, the knockdown of SLC1A4 or simple suppl...