MSCs-derived EVs protect against chemotherapy-induced ovarian toxicity: role of PI3K/AKT/mTOR axis

被引:0
作者
Elsherbiny, Nehal M. [1 ]
Abdel-Maksoud, Mohamed S. [2 ]
Prabahar, Kousalya [3 ]
Mohammedsaleh, Zuhair M. [4 ]
Badr, Omnia A. M. [5 ]
Dessouky, Arigue A. [6 ]
Salem, Hoda A. [3 ]
Refadah, Omnia A. [7 ]
Farid, Ayman Samir [8 ]
Shamaa, Ashraf A. [9 ]
Ebrahim, Nesrine [10 ,11 ,12 ,13 ]
机构
[1] Univ Tabuk, Fac Pharm, Dept Pharmaceut Chem, Tabuk, Saudi Arabia
[2] Univ Tabuk, Fac Pharm, Dept Pharmacol & Toxicol, Tabuk, Saudi Arabia
[3] Univ Tabuk, Fac Pharm, Dept Pharm Practice, Tabuk, Saudi Arabia
[4] Univ Tabuk, Fac Appl Med Sci, Dept Med Lab Technol, Tabuk 71491, Saudi Arabia
[5] Benha Univ, Fac Agr, Dept Genet & Genet Engn, Banha, Egypt
[6] Zagazig Univ, Fac Med, Dept Med Histol & Cell Biol, Zagazig 44519, Egypt
[7] Univ Tabuk, Fac Pharm, PharmD Program, Tabuk, Saudi Arabia
[8] Benha Univ, Fac Vet Med, Dept Clin Pathol, Moshtohor 13736, Qalyubia, Egypt
[9] Cairo Univ, Fac Vet Med, Surg Anesthesiol & Radiol Dept, Cairo, Egypt
[10] Benha Univ, Fac Med, Dept Med Histol & Cell Biol, Banha, Egypt
[11] Benha Univ, Fac Med, Stem Cell Unit, Banha, Egypt
[12] Benha Natl Univ, Fac Med, Al Obour City, Egypt
[13] Keele Univ, Sch Pharm & Bioengn, Keele, England
关键词
Fertility preservation; Chemotherapy; Ovaries; MSCs-derived exosomes; PI3K/Akt/; mTOR; EXTRACELLULAR VESICLES; SIGNALING PATHWAY; FERTILITY PRESERVATION; MECHANISMS; ACTIVATION; EXOSOMES; RESERVE; CANCER; DAMAGE; CELLS;
D O I
10.1186/s13048-024-01545-7
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Chemotherapy detrimentally impacts fertility via depletion of follicular reserves in the ovaries leading to ovarian failure (OF) and development of estrogen deficiency-related complications. The currently proposed options to preserve fertility such as Oocyte or ovarian cortex cryopreservation are faced with many technical obstacles that limit their effective implementation. Therefore, developing new modalities to protect ovarian function remains a pending target. Exosomes are nano-sized cell-derived extracellular vesicles (EVs) with documented efficacy in the field of regenerative medicine. The current study sought to determine the potential beneficial effects of mesenchymal stem cells (MSCs)-derived EVs in experimentally induced OF. Female albino rats were randomly allocated to four groups: control, OF group, OF + MSCs-EVs group, OF + Rapamycin (mTOR inhibitor) group, and OF + Quercetin (PI3K/AKT inhibitor) group. Follicular development was assessed via histopathological and immunohistochemical examination, and ovarian function was evaluated by hormonal assay. PI3K/Akt/mTOR signaling pathway as a key modulator of ovarian follicular activation was also assessed. MSCs-EVs administration to OF rats resulted in restored serum hormonal levels, preserved primordial follicles and oocytes, suppressed ovarian PI3K/AKT axis and downstream effectors (mTOR and FOXO3), modulated miRNA that target this axis, decreased expression of ovarian apoptotic markers (BAX, BCl2) and increased expression of proliferation marker Ki67. The present study validated the effectiveness of MSCs-EVs therapy in preventing ovarian insufficiency induced by chemotherapy. Concomitant MSCs-EVs treatment during chemotherapy could significantly preserve ovarian function and fertility by suppressing the PI3K/Akt axis, preventing follicular overactivation, maintaining normal ovarian cellular proliferation, and inhibiting granulosa cell apoptosis.
引用
收藏
页数:15
相关论文
共 56 条
  • [1] Molecular Mechanisms Underlying the Activation of Mammalian Primordial Follicles
    Adhikari, Deepak
    Liu, Kui
    [J]. ENDOCRINE REVIEWS, 2009, 30 (05) : 438 - 464
  • [2] Exploring the cytoprotective role of mesenchymal stem Cell-Derived exosomes in chronic liver Fibrosis: Insights into the Nrf2/Keap1/p62 signaling pathway
    Al Saihati, Hajir A.
    Badr, Omnia A.
    Dessouky, Arigue A.
    Mostafa, Ola
    Farid, Ayman Samir
    Aborayah, Nashwa H.
    Aljasir, Mohammad Abdullah
    Baioumy, Bodour
    Taha, Neama Mahmoud
    El-Sherbiny, Mohamed
    Al-Serwi, Rasha Hamed
    Ramadan, Mahmoud M.
    Salim, Rabab F.
    Shaheen, Dalia
    Ali, Fares E. M.
    Ebrahim, Nesrine
    [J]. INTERNATIONAL IMMUNOPHARMACOLOGY, 2024, 141
  • [3] Preservation of fertility in female: Indications, available options, and current status in Saudi Arabia
    Aljaser, Feda
    [J]. SEMINARS IN ONCOLOGY, 2020, 47 (06) : 390 - 397
  • [4] Signaling pathway intervention in premature ovarian failure
    Bai, Xuefeng
    Wang, Shaowei
    [J]. FRONTIERS IN MEDICINE, 2022, 9
  • [5] QuPath: Open source software for digital pathology image analysis
    Bankhead, Peter
    Loughrey, Maurice B.
    Fernandez, Jose A.
    Dombrowski, Yvonne
    Mcart, Darragh G.
    Dunne, Philip D.
    McQuaid, Stephen
    Gray, Ronan T.
    Murray, Liam J.
    Coleman, Helen G.
    James, Jacqueline A.
    Salto-Tellez, Manuel
    Hamilton, Peter W.
    [J]. SCIENTIFIC REPORTS, 2017, 7
  • [6] Extracellular vesicle mediated intercellular communication at the porcine maternal-fetal interface: A new paradigm for conceptus-endometrial cross-talk
    Bidarimath, Mallikarjun
    Khalaj, Kasra
    Kridli, Rami T.
    Kan, Frederick W. K.
    Koti, Madhuri
    Tayade, Chandrakant
    [J]. SCIENTIFIC REPORTS, 2017, 7
  • [7] Mechanisms of DNA Damage, Repair, and Mutagenesis
    Chatterjee, Nimrat
    Walker, Graham C.
    [J]. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, 2017, 58 (05) : 235 - 263
  • [8] Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage
    Chen, Xiuying
    Tang, Zhijing
    Guan, Haiyun
    Xia, Hexia
    Gu, Chao
    Xu, Yan
    Li, Bin
    Zhang, Wei
    [J]. JOURNAL OF REPRODUCTION AND DEVELOPMENT, 2022, 68 (04) : 287 - 294
  • [9] The regulatory effect of Genistein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways
    Chi, Xiao-Xing
    Zhang, Tao
    Chu, Xiao-Li
    Zhen, Jing-Long
    Zhang, Dong-Jie
    [J]. JOURNAL OF VETERINARY MEDICAL SCIENCE, 2018, 80 (08) : 1348 - 1355
  • [10] Stem cell-based therapeutic potential in female ovarian aging and infertility
    Cui, Xiangrong
    Jing, Xuan
    [J]. JOURNAL OF OVARIAN RESEARCH, 2024, 17 (01)