人脐带间充质干细胞通过减轻铁死亡改善顺铂诱导的小鼠血睾屏障功能障碍。

Human umbilical cord mesenchymal stem cells ameliorates cisplatin-induced blood-testis barrier dysfunction in mice by mitigating ferroptosis.

作者信息

Liu XueXia, Wang XiaoXin, Zhang XueYing, Zhang YuXiao, Gong BenJiao, Zhu Peng, Liu FuJun

机构信息

Shandong Stem Cell Engineering Technology Research Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.

School of Bioscience and Technology, Shandong Second Medical University, Weifang, China.

出版信息

Stem Cell Res Ther. 2025 Sep 26;16(1):511. doi: 10.1186/s13287-025-04645-3.

DOI:10.1186/s13287-025-04645-3

PMID:41013667

Abstract

BACKGROUND

Cisplatin (CDDP), a widely used chemotherapeutic agent, induces reproductive toxicity primarily by damaging the blood-testis barrier (BTB) and triggering oxidative stress. This study aimed to investigate whether human umbilical cord mesenchymal stem cells (hUC-MSCs) protect against CDDP-induced BTB dysfunction and ferroptosis in mice, with implications for preserving fertility in chemotherapy patients.

METHODS

Male C57 mice were randomized into four groups: control, CDDP-treated, hUC-MSCs-treated, and CDDP+hUC-MSCs-treated. An additional CDDP+Ferrostatin-1 (Fer-1, a ferroptosis inhibitor) group was included to validate ferroptosis involvement. Testicular histology, sperm quality, BTB integrity (via Evans blue permeability assay), and oxidative stress markers were evaluated. Ferroptosis-related (GPX4, NRF2, COX2, TFR1) and BTB-related (N-cadherin, ZO-1, Connexin 43) proteins were assessed by immunofluorescence and Western blotting. In vitro fertilization (IVF) was used to evaluate fertility.

RESULTS

CDDP induced significant testicular damage, reduced sperm quality, increased BTB permeability, and disrupted BTB proteins. It also triggered ferroptosis, as evidenced by decreased GSH, elevated MDA, downregulated GPX4/NRF2, and upregulated COX2/TFR1. hUC-MSCs reversed these changes: restoring GSH levels, reducing MDA, normalizing ferroptosis-related proteins, and repairing BTB integrity. Fer-1 mimicked these effects, confirming ferroptosis as a key mechanism. IVF showed hUC-MSCs restored embryonic development (two-cell and blastocyst rates) to normal.

CONCLUSIONS

hUC-MSCs protect against CDDP-induced reproductive injury by inhibiting ferroptosis (especially in Sertoli cells), repairing BTB, and restoring fertility. Their transient retention and low immunogenicity support their potential as a safe therapeutic strategy for preserving fertility in chemotherapy patients.

摘要

背景

顺铂（CDDP）是一种广泛使用的化疗药物，主要通过破坏血睾屏障（BTB）和引发氧化应激来诱导生殖毒性。本研究旨在探讨人脐带间充质干细胞（hUC-MSCs）是否能保护小鼠免受CDDP诱导的BTB功能障碍和铁死亡，这对化疗患者的生育力保护具有重要意义。

方法

将雄性C57小鼠随机分为四组：对照组、CDDP处理组、hUC-MSCs处理组和CDDP+hUC-MSCs处理组。另外设置一个CDDP+铁死亡抑制剂Ferrostatin-1（Fer-1）组以验证铁死亡的参与情况。评估睾丸组织学、精子质量、BTB完整性（通过伊文思蓝通透性测定）和氧化应激标志物。通过免疫荧光和蛋白质印迹法评估铁死亡相关蛋白（GPX4、NRF2、COX2、TFR1）和BTB相关蛋白（N-钙黏蛋白、ZO-1、连接蛋白43）。采用体外受精（IVF）评估生育力。

结果

CDDP诱导了显著的睾丸损伤，降低了精子质量，增加了BTB通透性，并破坏了BTB蛋白。它还引发了铁死亡，表现为谷胱甘肽（GSH）降低、丙二醛（MDA）升高、GPX4/NRF2下调以及COX2/TFR1上调。hUC-MSCs逆转了这些变化：恢复了GSH水平，降低了MDA，使铁死亡相关蛋白正常化，并修复了BTB完整性。Fer-1模拟了这些作用，证实铁死亡是关键机制。IVF显示hUC-MSCs将胚胎发育（二细胞和囊胚率）恢复到正常水平。