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BDNF secreted by mesenchymal stem cells improves the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway

ABSTRACT: Decreased oocyte quality is a major determinant of age-associated fertility decline which lacks an effective treatment strategy. The secretome of mesenchymal stem cells (MSC-sec) contains various bioactive factors and has the potential to improve oocyte quality. In this study, MSC-sec treatment significantly increased first polar body emission, improved spindle assembly, reduced aneuploidy rate, and promoted maternal mRNA degradation in aged mouse oocytes, whereas the addition of BDNF antibody blocked the effects of MSC-sec. Furthermore, BDNF treatment alone also improved the oocyte quality from aged mice. Mechanistically, both MSC-sec and BDNF activated the ERK1/2 signaling pathway to increase the expression of DAZL and BTG4 in aged oocytes. Furthermore, injection of MSC-sec or BDNF into aged mouse ovaries significantly improved oocyte quality and early embryonic development. Finally, we demonstrated that BDNF treatment increased both the fertilization rate and blastocyst formation of aged human oocytes. Our study identified BDNF as the functional component of MSC-sec to improve the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway, suggesting that BDNF has the potential to mitigate age-related decline in oocyte quality.

ORGANISM(S): Mus musculus

PROVIDER: GSE263864 | GEO | 2025/04/02

REPOSITORIES: GEO

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Project description:BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

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BDNF secreted by mesenchymal stem cells improves the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway

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