The substantial apprehension facing young cancer patients revolves around the onset of chemotherapy-induced premature ovarian failure (POF), primarily linked to damage inflicted upon granulosa cells (GCs). The inquiry delves into the protective role of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in mitigating chemotherapy-induced ovarian failure. Specifically, we investigated the mechanism by which hUCMSC-EVs deliver the long non-coding RNA (lncRNA) HCP5 to regulate DNA damage repair in GCs via the miR-20a-5p/YAP1 axis. The detection of differentially expressed lncRNAs in GC injury resulting from cyclophosphamide (CP) was conducted through transcriptome sequencing. hUCMSC-EVs were isolated, characterized, and co-cultured with CP-injured GCs. Functional assays such as CCK-8, TUNEL, and ELISA were performed to evaluate GC viability, apoptosis, and ovarian endocrine function. Experimental validation of the interactions involving HCP5, miR-20a-5p, and YAP1 was achieved through performing luciferase reporter assays, RNA immunoprecipitation experiments, and Western blot (WB) analyses. HCP5 was significantly enriched in hUCMSC-EVs and effectively delivered into GCs. This resulted in improved GC viability, reduced apoptosis, and enhanced DNA repair. Mechanistically, HCP5 sponged miR-20a-5p, leading to the upregulation of YAP1, which in turn mitigated CP-induced GC damage. In vivo experiments further demonstrated that hUCMSC-EVs prevented CP-induced POF through modulation of the HCP5-miR-20a-5p-YAP1 axis. Our research underscores the therapeutic potential of hUCMSC-EVs in delivering HCP5 to promote DNA repair in GCs, thereby preventing chemotherapy-induced POF. This study provides a novel molecular framework for future therapeutic strategies aimed at protecting ovarian function during chemotherapy. Graphical abstract Graphical Headlights<OrderedList> <ListItem> <ItemNumber>1.</ItemNumber> <ItemContent> hUCMSC-EVs protect GCs by delivering HCP5, mitigating chemotherapy-induced POF. </ItemContent> </ListItem> <ListItem> <ItemNumber>2.</ItemNumber> <ItemContent> HCP5 sponges miR-20a-5p, upregulating YAP1 to promote DNA repair in GCs. </ItemContent> </ListItem> <ListItem> <ItemNumber>3.</ItemNumber> <ItemContent> Overexpression of miR-20a-5p reverses the protective effects of HCP5. </ItemContent> </ListItem> <ListItem> <ItemNumber>4.</ItemNumber> <ItemContent> This study highlights a novel mechanism and therapeutic strategy for preserving ovarian function during chemotherapy. </ItemContent> </ListItem> </OrderedList>

Mitigating chemotherapy-induced granulosa cell damage: role of hUCMSC-EVs in regulating the lncRNA HCP5-miR-20a-5p-YAP1 network

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2025年5月2日

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Ying Xie,
Xiaoqin Chen,
Tong Liang,
Ling Chen,
Dan Liu

摘要

The substantial apprehension facing young cancer patients revolves around the onset of chemotherapy-induced premature ovarian failure (POF), primarily linked to damage inflicted upon granulosa cells (GCs). The inquiry delves into the protective role of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in mitigating chemotherapy-induced ovarian failure. Specifically, we investigated the mechanism by which hUCMSC-EVs deliver the long non-coding RNA (lncRNA) HCP5 to regulate DNA damage repair in GCs via the miR-20a-5p/YAP1 axis. The detection of differentially expressed lncRNAs in GC injury resulting from cyclophosphamide (CP) was conducted through transcriptome sequencing. hUCMSC-EVs were isolated, characterized, and co-cultured with CP-injured GCs. Functional assays such as CCK-8, TUNEL, and ELISA were performed to evaluate GC viability, apoptosis, and ovarian endocrine function. Experimental validation of the interactions involving HCP5, miR-20a-5p, and YAP1 was achieved through performing luciferase reporter assays, RNA immunoprecipitation experiments, and Western blot (WB) analyses. HCP5 was significantly enriched in hUCMSC-EVs and effectively delivered into GCs. This resulted in improved GC viability, reduced apoptosis, and enhanced DNA repair. Mechanistically, HCP5 sponged miR-20a-5p, leading to the upregulation of YAP1, which in turn mitigated CP-induced GC damage. In vivo experiments further demonstrated that hUCMSC-EVs prevented CP-induced POF through modulation of the HCP5-miR-20a-5p-YAP1 axis. Our research underscores the therapeutic potential of hUCMSC-EVs in delivering HCP5 to promote DNA repair in GCs, thereby preventing chemotherapy-induced POF. This study provides a novel molecular framework for future therapeutic strategies aimed at protecting ovarian function during chemotherapy.

Graphical abstract

Graphical Headlights 1.

hUCMSC-EVs protect GCs by delivering HCP5, mitigating chemotherapy-induced POF.

HCP5 sponges miR-20a-5p, upregulating YAP1 to promote DNA repair in GCs.

Overexpression of miR-20a-5p reverses the protective effects of HCP5.

This study highlights a novel mechanism and therapeutic strategy for preserving ovarian function during chemotherapy.