bims-ovagas 2026-04-12 papers

NPJ Aging. 2026 Apr 04.

Extracellular matrix: new insights into its role in female reproductive aging and potential therapeutic strategies.

Ning Lu, Jing Wang, Yi-Hui Li, Xu-Hui Fang, Yu-Ting Peng, Qing-Peng Luo, Ai-Hua Liao.

Extracellular matrix (ECM), once regarded as a passive structural scaffold, is now recognized as a key hallmark of aging. In the context of female reproductive aging, ECM remodeling acts as a pivotal driver of functional deterioration. This review outlines how age-associated ECM alterations, including collagen cross-linking, elastin degradation, and perturbed biomechanics, orchestrate ovarian aging through the mechanical activation of Hippo signaling, compromise endometrial receptivity via dysregulated matrix metalloproteinase activity, and impair embryo invasion by altering ligand presentation. We also discuss emerging ECM-targeted strategies, such as decellularized scaffolds, engineered hydrogels, and 3D-bioprinted matrices, which have demonstrated potential for rejuvenating reproductive function in preclinical models. Furthermore, matrisome-based biomarkers provide novel prognostic insights into reproductive outcomes. Collectively, these advances identify the ECM as a promising target for innovative, non-hormonal interventions aimed at extending female reproductive longevity.

DOI: https://doi.org/10.1038/s41514-026-00371-z

bioRxiv. 2026 Apr 01. pii: 2025.12.04.692166. [Epub ahead of print]

Determining the age of single cells using scMLEAge.

Chanyue Hu, Matteo Pellegrini.

1 Aging is a complex biological process marked by a gradual decline in physiological function that contributes to increased vulnerability to disease and mortality. Numerous studies have investigated the cellular and molecular aspects of aging at single-cell resolution, yet the heterogeneity of cellular aging in an individual remains poorly understood. To enhance our ability to study aging at the single cell level, we developed a statistical framework to predict the age of individual cells based on their transcriptomic profiles. Our Bayesian approach estimates the most likely age of a cell given its read counts. We applied the model to data from Tabula Muris Senis and examined organ- and cell-type-specific transcriptomic signatures of aging. Compared with standard regression-based methods, our framework achieved higher predictive accuracy. We show that scMLEAge is a powerful tool for dissecting the cellular heterogeneity of aging and age-related functional decline.

DOI: https://doi.org/10.64898/2025.12.04.692166

bioRxiv. 2026 Apr 01. pii: 2026.03.30.715371. [Epub ahead of print]

NFYA regulates two sequential genome-wide transcriptional activation events during oocyte to embryo transition.

Qianying Yang, Shan Jiang, Boyan Wang, Yi Zhang.

Primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA) represent two major waves of transcription activation respectively required for oocyte growth and preimplantation embryo development. Although many shared molecular hallmarks between PFA and ZGA suggest potential common factors and mechanisms driving both waves of transcriptional activation, such factors are yet to be identified. Here we demonstrate that the pioneer factor NFYA belongs to such regulators. Oocyte-specific Nfya deletion impairs open chromatin establishment and transcriptional activation during PFA, which triggers non-canonical ferroptosis leading to early folliculogenesis failure. Moreover, acute NFYA depletion in zygotes causes defective ZGA and predominantly two-cell embryo arrest. Mechanistically, although NFYA exhibits distinct chromatin-binding preferences predominantly targeting promoters during PFA and enhancers during ZGA, pre-occupied NFYA regulates chaperones and histone genes in both PFA and ZGA through conserved promoter binding. Together, our studies establish NFYA as a multifaceted regulator of genome activation during both PFA and ZGA.
Highlights: NFYA deficiency impairs primordial follicle oocyte activation (PFA) and triggers non-canonical ferroptosis resulting in early folliculogenesis failureNFYA depletion impairs zygotic genome activation (ZGA) and causes predominantly 2-cell embryo arrestConserved and distinct NFYA-chromatin interactions drive both PFA and ZGAChaperones are pre-occupied and regulated by NFYA and their inhibition impairs both PFA and ZGA.

DOI: https://doi.org/10.64898/2026.03.30.715371

Stem Cell Res Ther. 2026 Apr 07.

Isorhamnetin-preconditioned MSC-derived exosomes restore ovarian function by inhibiting ferroptosis in chemotherapy-induced POF.

Qiang Zhang, Jinyu Yu, Yan Zheng, Jinlan Jiang, Lianwen Zheng.

BACKGROUND: Chemotherapy-induced premature ovarian failure (POF) is a major cause of infertility, with limited treatment options. Mesenchymal stem cell-derived exosomes (MSC-Exos) have therapeutic potential. This study investigated whether preconditioning MSCs with the antioxidant flavonoid isorhamnetin (ISO) enhances the efficacy of their exosomes (ISO-MSC-Exos) against POF.
METHODS: A cyclophosphamide-induced POF rat model was established, and the role of the ferroptosis inhibitor ferrostatin-1 was evaluated. MSC-Exos and ISO-MSC-Exos were isolated by ultracentrifugation and administered via tail vein injection. Ovarian recovery was assessed by monitoring the oestrous cycle, serum hormone levels, and histological findings. Lipid peroxidation and iron metabolism were evaluated by quantifying malondialdehyde, glutathione, iron deposition, and mitochondrial ultrastructure. Immunohistochemistry was used to assess the expression levels of GPX4, ACSL4, and FTH1. Proteomic analyses were performed to explore the underlying mechanisms.
RESULTS: Ferroptosis plays a pivotal role in the cyclophosphamide-induced POF rat model. Both exosome therapies improved ovarian function and suppressed ferroptosis, with ISO-MSC-Exos showing superior efficacy. ISO-MSC-Exos significantly restored hormone levels, ameliorated oestrous cycle disorders, reduced follicular atresia, and enhanced fertility. Furthermore, ISO-MSC-Exos more effectively elevated glutathione levels, reduced malondialdehyde and Fe2⁺ levels, and reversed the abnormal expression of ferroptosis-related proteins GPX4, ACSL4, and FTH1. Proteomic analysis suggested that ISO-MSC-Exos effectively inhibit ferroptosis by downregulating Alox15 and Tf, thereby reducing lipid peroxidation substrates and cellular iron uptake. This finding represents a potential molecular mechanism underlying their superior efficacy compared with that of MSC-Exos.
CONCLUSIONS: ISO-MSC-Exos showed superior efficacy compared with MSC-Exos in restoring ovarian function and inhibiting ferroptosis, suggesting that ISO pretreatment enhances the therapeutic effect of MSC-Exos in the POF model. Proteomic data provided supportive mechanistic insights into this enhanced efficacy, with the key pathways identified requiring subsequent functional validation.

Keywords: Exosomes; Ferroptosis; Isorhamnetin; Mesenchymal stem cells; Premature ovarian failure

DOI: https://doi.org/10.1186/s13287-026-04989-4

bioRxiv. 2026 Mar 30. pii: 2026.03.28.714908. [Epub ahead of print]

Critical roles of MCM8 in meiotic recombination during mouse spermatogenesis.

Lava Kumar Surarapu, Kevin Tilton, Maria Rosaria Dello Stritto, Ananya Acharya, Andrea Marton Menendez, Min Lu, Najma Shaheen, Shun Liang, Mythri Iyer, Petr Cejka, Florencia Pratto, Devanshi Jain.

Meiotic DNA double-strand break (DSB) formation and repair by homologous recombination is crucial for ensuring proper chromosome segregation. In mice, the mini-chromosome maintenance family protein, MCM8, has been proposed to function in meiotic recombination and its loss leads to infertility, but the underlying mechanisms are poorly understood. Here we used cytological and genomic assays to infer the role of MCM8 during meiotic recombination in mouse spermatocytes. We show that MCM8-deficient spermatocytes exhibit increased levels of SPO11-dependent DSBs at recombination hotspots during early prophase. DSBs are resected normally and accumulate strand-exchange proteins. However, downstream recombination intermediates are barely detected and recombination intermediate-associated MutSgamma foci do not form efficiently. Consistent with a role in early recombination intermediate processing, MCM8 binds to displacement loop (D-loop) structures in vitro . We propose that MCM8 controls meiotic recombination in at least two ways. MCM8 participates in regulating meiotic DSB number. Further, MCM8 plays a role in the formation and/or stability of post-resection recombination intermediates, steps that are critical for DSB repair via recombination and for efficient synapsis of homologous chromosomes during mouse meiosis.

DOI: https://doi.org/10.64898/2026.03.28.714908