Exosomes derived from mesenchymal stem cells attenuate NLRP3-related pyroptosis in autoimmune premature ovarian insufficiency via the NF-κB pathway

Jiaxin Xie; Yutao Yang; Aiping Zhuo; Meng Gao; Lichao Tang; Yuanling Xiao; Honglei Zhu; Xiafei Fu

doi:10.1016/j.rbmo.2024.103814

Exosomes derived from mesenchymal stem cells attenuate NLRP3-related pyroptosis in autoimmune premature ovarian insufficiency via the NF-κB pathway

Reprod Biomed Online. 2024 Jan 9;48(6):103814. doi: 10.1016/j.rbmo.2024.103814. Online ahead of print.

Authors

Jiaxin Xie¹, Yutao Yang¹, Aiping Zhuo¹, Meng Gao¹, Lichao Tang¹, Yuanling Xiao¹, Honglei Zhu¹, Xiafei Fu²

Affiliations

¹ Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guanazhou, Guangdong, China.
² Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guanazhou, Guangdong, China. Electronic address: fxf1997@smu.edu.cn.

PMID: 38569224
DOI: 10.1016/j.rbmo.2024.103814

Abstract

Research question: What is the effect of exosomes derived from bone marrow mesenchymal stem cells (MSC-Exos) on the pyroptosis and recovery of granulosa cells in autoimmune premature ovarian insufficiency (POI)?

Design: In vitro, KGN cells were exposed to interferon-gamma to simulate immune injury. Samples were collected after a 48 h incubation with MSC-Exos (30 μg/ml). The cell viability, secretion of oestrogen and expression of key molecules in pyroptosis and the nuclear factor kappa B (NF-κB) pathway were tested. In vivo, the BALB/c mouse model of autoimmune POI model induced by zona pellucida glycoprotein 3 was used. Fertility testing and sample collection were applied 4 weeks after the ovarian subcapsular injection of MSC-Exos (150 μg for each ovary). Hormone concentration measurements, follicle counting and pyroptotic pathway analyses were conducted for each group.

Results: In vitro, MSC-Exos significantly promoted the proliferation rate and secretion of oestrogen, while at the same time suppressing apoptosis and pyroptosis. In vivo, exosomal treatment normalized the irregular oestrous cycles, rescued the follicular loss and increased the pregnancy rate and number of offspring in POI mice. Elevated serum concentrations of oestrogen and anti-Müllerian hormone, as well as decreased concentrations of FSH and interleukin-1β, were shown. Furthermore, MSC-Exos down-regulated the expression of the NLRP3/Casp1/GSDMD pathway and inhibited activation of the NF-κB pathway.

Conclusions: These findings demonstrate for the first time that MSC-Exos exert a significant effect on restoring ovarian function in autoimmune POI in vivo and in vitro by suppressing the NLRP3/Casp1/GSDMD pathway and pyroptosis. The NF-κB pathway may contribute to the regulation of NLRP3-related pyroptosis.

Keywords: Exosome; Mesenchymal stem cells; NLRP3; Nuclear factor kappa B (NF-κB) pathway; Premature ovarian insufficiency; Pyroptosis.