Hypoxic mesenchymal stem cell-Derived Exosomal circPTP4A2 improves granulosa cell mitochondrial function via YBX1

Area of Science:

• Reproductive Biology
• Cellular and Molecular Medicine
• Regenerative Medicine

Background:

• Premature ovarian insufficiency (POI) severely impacts female reproductive health due to accelerated follicle loss and hormonal imbalances.
• Mesenchymal stem cell-derived exosomes (MSC-Exs) show therapeutic potential for POI, with hypoxic preconditioning enhancing their efficacy.
• This study investigates hypoxia-preconditioned MSC-Exs (H-Exs) for their ability to protect granulosa cells (GCs) from oxidative damage and restore ovarian function in a POI rat model.

Purpose of the Study:

• To evaluate the therapeutic potential of H-Exs in ameliorating oxidative stress and restoring ovarian function in a POI model.
• To elucidate the underlying molecular mechanisms, focusing on the role of specific exosomal circRNAs.
• To identify and validate the circPTP4A2/YBX1 axis as a key mediator of H-Exs' therapeutic effects.

Main Methods:

• Identification and validation of circRNAs enriched in H-Exs.
• Assessment of H-Exs and circPTP4A2 effects on GC oxidative damage and mitochondrial function using various assays (ROS, JC-1, ATP, OCR).
• Analysis of the circPTP4A2/YBX1 interaction and the role of the hypoxia-inducible factor 1-alpha (HIF-1α) in regulating circPTP4A2 expression.

Main Results:

• H-Exs demonstrated superior protective effects compared to normoxic MSC-Exs (N-Exs), significantly reducing oxidative stress and improving mitochondrial function in GCs.
• circPTP4A2 was identified as a key hypoxia-responsive cargo in H-Exs, stabilizing YBX1 and enhancing its antioxidative and mitochondrial regulatory functions.
• HIF-1α was found to transcriptionally upregulate circPTP4A2 by binding to the promoter of its host gene, PTP4A2.

Conclusions:

• The circPTP4A2/YBX1 axis is a critical mediator of H-Exs' therapeutic efficacy in POI.
• These findings provide mechanistic insights into exosome-based regenerative strategies for POI.
• The study establishes a translational framework for utilizing H-Exs in treating POI.