Subcutaneous delivery of icariin via a gelatin methacryloyl(GelMA)hydrogel sustained-release system improves ovarian function in reproductively aged miceOACSCDCSTPCD
Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian restoration.In this study,a subcutaneous implantation system using gelatin methacryloyl(GelMA)hydrogel embedded with ICA was developed to restore ovarian function in aged female mice.Mice were assigned to receive subcutaneous implantation of GelMA alone(GelMA group),GelMA containing ICA(GelMA/ICA group),or a sham operation.Ovarian morphology,serum hormone levels,follicle counts across developmental stages,and reproductive outcomes were evaluated.In vitro fertilization(IVF)and embryo culture assays were performed to assess oocyte developmental potential,while a 10 day natural mating trial was conducted to determine fertility restoration.RNA sequencing(RNA-seq)and RT-qPCR were performed to elucidate the underlying molecular mechanisms.Results showed that GelMA/ICA treatment significantly increased ovarian index(0.19±0.01 vs.0.13±0.01,P<0.0001)and follicle numbers at all developmental stages,including primordial(383.33±151.65 vs.107.14±32.26,P<0.0001),primary(203.33±83.22 vs.91.43±27.04,P=0.003),and secondary follicles(154.17±52.00 vs.59.28±20.50,P=0.029)compared to the sham controls.Hormonal analyses revealed a significant reduction in serum follicle-stimulating hormone(FSH,11.97±3.53 vs.53.10±17.89 ng/mL,P=0.0008),accompanied by elevated anti-Müllerian hormone(AMH,22.97±2.26 vs.5.54±1.56 ng/mL,P<0.0001)and estradiol(E2,315.30±37.62 vs.168.5±14.78 pg/mL,P<0.0001).Oocyte yield and developmental potential improved significantly,as reflected by the increased number of superovulated MII oocytes(17.83±5.15 vs.4.83±4.79,P=0.0002),and higher proportions of two-cell(85.90%±6.16%vs.50.00%±10.00%,P=0.0009),four-cell(81.67%±9.76%vs.50.00%±10.00%,P=0.0061),and blastocyst stage embryos(64.25%±10.55%vs.23.33%±15.28%,P=0.0067).Live birth numbers were significantly increased following GelMA/ICA treatment(6.90±3.21 vs.1.72±2.05,P=0.0001).Transcriptomic analysis revealed up-regulation of genes associated with cytoskeletal organization(Vil1,Tubb3),lipid storage(Soat2,Plin4),oocyte maturation(Oosp2),and cytokine secretion(Cxcl12).Collectively,these findings suggest that GelMA/ICA hydrogels effectively reverse key hallmarks of ovarian aging and restore reproductive function in aged mice,offering a promising platform for fertility preservation and a novel therapeutic for future investigations into ovarian aging.
Jia-Lian Mao;Xiang-Yi Wu;Ling-Xi Li;Ning Li;Ya-Xuan Wang;Zhi-Wei Jiang;Chuan-Ming Liu;Hui-Dan Zhang;Ji-Dong Zhou;Yang Zhang;Li Chen;Gui-Jun Yan;Hai-Xiang Sun;Yi-Fan Li;Li-Jun Ding
Center for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing University of Chinese Medicine,Nanjing,Jiangsu 210008,ChinaDepartment of Plastic and Reconstructive Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing University of Chinese Medicine,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing University of Chinese Medicine,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing Medical University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing University of Chinese Medicine,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,ChinaCenter of Reproductive Medicine,Changzhou Maternal and Child Health Care Hospital,Changzhou,Jiangsu 213003,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,China State Key Laboratory of Reproductive Medicine and Offspring Health,Center for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,ChinaCenter for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing University of Chinese Medicine,Nanjing,Jiangsu 210008,China Center for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Clinical College of Nanjing Medical University,Nanjing,Jiangsu 210008,China Center for Reproductive Medicine and Obstetrics and Gynecology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China Center for Molecular Reproductive Medicine,Nanjing University,Nanjing,Jiangsu 210008,China Clinical Center for Stem Cell Research,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China State Key Laboratory of Analytic Chemistry for Life Science,Nanjing University,Nanjing,Jiangsu 210023,China
医药卫生
Ovarian agingIcariinSubcutaneous implantationGelMAOvarian reserve
《Zoological Research》 2025 (4)
P.863-876,14
supported by the National Natural Science Foundation of China(82271671)Nanjing Drum Tower Hospital Academic Innovation Peak Fund(2024-DF-02)Clinical Trials from Nanjing Drum Tower Hospital(2023-LCYJ-MS-05)Nanjing International Science and Technology Cooperation Program(202201027)to L.D.Research Project of State Key Laboratory of Reproductive Medicine and Offspring Health(SKLRM-2022D2)Changzhou Medical Center of Nanjing Medical University(CMCM202203)Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-02)to H.S.
评论