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

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.