Research Progress on Exosomes in the Diagnosis and Treatment of Premature Ovarian Failure

doi:10.12280/gjfckx.20240378

Abstract

Abstract:

Premature ovarian failure (POF) is an endocrine disorder with an increasing incidence in recent years, often leading to decreased female fertility and various postmenopausal symptoms. The etiology of POF remains unclear, and current treatment options are limited, necessitating new approaches to improve ovarian function and enhance fertility in affected women. Exosomes are nano-vesicles that carry a variety of active substances and participate in intercellular signal transmission, exhibiting strong targeting and specificity. Studies have revealed significant differences in certain exosomes between normal and PDF tissues, suggesting their potential as biomarkers for diagnosing POF. Additionally, exosomes may play a crucial role in POF treatment by affecting granulosa cells, promoting hormone secretion, angiogenesis, and combating oxidative stress. This review summarizes the research progress on the relationship between exosomes and POF, aiming to provide a reference for future studies on the role of exosomes in POF.

Key words: Primary ovarian insufficiency, Exosomes, Diagnosis, Therapy

GUO Pei-yi, ZHU Xue-hong, LIU Hui-xing, LU Li-miao, LIN Zhong. Research Progress on Exosomes in the Diagnosis and Treatment of Premature Ovarian Failure[J]. Journal of International Obstetrics and Gynecology, 2024, 51(5): 492-496.

Figures/Tables 1

References 37

[1]	中华医学会妇产科学分会绝经学组. 早发性卵巢功能不全的临床诊疗专家共识(2023版)[J]. 中华妇产科杂志, 2023, 58(10):721-728. doi: 10.3760/cma.j.cn112141-20230316-00122.
[2]	Jiang M, Gao Y, Hou H, et al. Bone mineral density in patients with primary ovarian insufficiency: A systematic review and Meta-Analysis[J]. Eur J Obstet Gynecol Reprod Biol, 2024, 295:219-227. doi: 10.1016/j.ejogrb.2024.02.013. pmid: 38387304
[3]	Zhang Z, Hu Y, Cui X, et al. Menopausal age and cardiovascular disease risk in American women: evidence from the National Health and Nutrition Examination Survey[J]. Climacteric, 2024, 27(2):159-164. doi: 10.1080/13697137.2023.2273526.
[4]	Ates S, Aydın S, Ozcan P, et al. Sleep, depression, anxiety and fatigue in women with premature ovarian insufficiency[J]. J Psychosom Obstet Gynaecol, 2022, 43(4):482-487. doi: 10.1080/0167482X.2022.2069008.
[5]	Huhtaniemi I, Hovatta O, La Marca A, et al. Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency[J]. Trends Endocrinol Metab, 2018, 29(6):400-419. doi: 10.1016/j.tem.2018.03.010.
[6]	Craciunas L, Zdoukopoulos N, Vinayagam S, et al. Hormone therapy for uterine and endometrial development in women with premature ovarian insufficiency[J]. Cochrane Database Syst Rev, 2022, 10(10):CD008209. doi: 10.1002/14651858.CD008209.pub2.
[7]	Sundell M, Brynhildsen J, Fredrikson M, et al. Insufficient use of menopausal hormone therapy in Swedish women with early or premature menopause caused by bilateral oophorectomy: a register-based study[J]. BJOG, 2024, 131(4):500-507. doi: 10.1111/1471-0528.17647.
[8]	史玉潇, 芦晓红, 卢望丁, 等. 外泌体的生物学性质及应用概述[J]. 中国医药工业杂志, 2023, 54(7):1008-1019. doi: 10.16522/j.cnki.cjph.2023.07.004.
[9]	Yin W, Ma H, Qu Y, et al. Targeted exosome-based nanoplatform for new-generation therapeutic strategies[J]. Biomed Mater, 2024 Mar 25;19(3). doi: 10.1088/1748-605X/ad3310.
[10]	Zhao X, Wang Q, Zhu G, et al. Size effect of cellulose nanocrystals in cellular internalization and exosome-packaging exocytosis[J]. Carbohydr Polym, 2022,298:120131. doi: 10.1016/j.carbpol.2022.120131.
[11]	Görgens A, Corso G, Hagey DW, et al. Identification of storage conditions stabilizing extracellular vesicles preparations[J]. J Extracell Vesicles, 2022, 11(6):e12238. doi: 10.1002/jev2.12238.
[12]	Li X, Gao T, Ma X, et al. Extraction and identification of exosomes from three different sources of human ovarian granulosa cells and analysis of their differential miRNA expression profiles[J]. J Assist Reprod Genet, 2024, 41(5):1371-1385. doi: 10.1007/s10815-024-03086-w.
[13]	Liang Y, Shuai Q, Zhang X, et al. Incorporation of Decidual Stromal Cells Derived Exosomes in Sodium Alginate Hydrogel as an Innovative Therapeutic Strategy for Advancing Endometrial Regeneration and Reinstating Fertility[J]. Adv Healthc Mater, 2024, 13(13):e2303674. doi: 10.1002/adhm.202303674.
[14]	Habib A, Liang Y, Zhu N. Exosomes multifunctional roles in HIV-1: insight into the immune regulation, vaccine development and current progress in delivery system[J]. Front Immunol, 2023,14:1249133. doi: 10.3389/fimmu.2023.1249133.
[15]	Xu WM, Li A, Chen JJ, et al. Research Development on Exosome Separation Technology[J]. J Membr Biol, 2023, 256(1):25-34. doi: 10.1007/s00232-022-00260-y.
[16]	Sharifian Gh M, Norouzi F. Guidelines for an optimized differential centrifugation of cells[J]. Biochem Biophys Rep, 2023,36:101585. doi: 10.1016/j.bbrep.2023.101585.
[17]	Ke X, Wang L, Duan L, et al. Comparison of PEG precipitation and ultrafiltration treatment for serum macroprolactin in Chinese patients with hyperprolactinemia[J]. Clin Chim Acta, 2023,544:117358. doi: 10.1016/j.cca.2023.117358.
[18]	Joncas-Schronce L, Ali F, Pepper G, et al. Evaluation of Three Cytomegalovirus IgG Lateral Flow Assays for Rapid Determination of CMV Serostatus[J]. Open Forum Infect Dis, 2024, 11(3):ofae084. doi: 10.1093/ofid/ofae084.
[19]	Dulong V, Rihouey C, Gaignard C, et al. Exopolysaccharide from marine microalgae belonging to the Glossomastix genus: fragile gel behavior and suspension stability[J]. Bioengineered, 2024, 15(1):2296257. doi: 10.1080/21655979.2023.2296257.
[20]	Zanini BM, de Avila BM, Garcia DN, et al. Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice[J]. Geroscience, 2024 Mar 19. doi: 10.1007/s11357-024-01129-9.
[21]	Zhang X, Zhang R, Hao J, et al. miRNA-122-5p in POI ovarian-derived exosomes promotes granulosa cell apoptosis by regulating BCL9[J]. Cancer Med, 2022, 11(12):2414-2426. doi: 10.1002/cam4.4615.
[22]	Sirotkin AV, Loncová B, Fabová Z, et al. Сopper nanoparticles supported on charcoal and betacellulin - Two novel stimulators of ovarian granulosa cell functions and their functional interrelationships[J]. Theriogenology, 2024, 218:137-141. doi: 10.1016/j.theriogenology.2024.01.028. pmid: 38325150
[23]	Tan J, Liu PP, Cao LY, et al. Reduced PATL2 Impairs the Proliferation of Ovarian Granulosa Cells by Decreasing ADM2 Expression in Patients with PCOS[J]. Reprod Sci, 2024, 31(4):1034-1044. doi: 10.1007/s43032-023-01420-8.
[24]	Chen W, E Q, Sun B, et al. PARP1-catalyzed PARylation of YY1 mediates endoplasmic reticulum stress in granulosa cells to determine primordial follicle activation[J]. Cell Death Dis, 2023, 14(8):524. doi: 10.1038/s41419-023-05984-w. pmid: 37582914
[25]	Liu B, Liu L, Sulaiman Z, et al. Comprehensive analysis of lncRNA-miRNA-mRNA ceRNA network and key genes in granulosa cells of patients with biochemical primary ovarian insufficiency[J]. J Assist Reprod Genet, 2024, 41(1):15-29. doi: 10.1007/s10815-023-02937-2.
[26]	Seok J, Park HS, Cetin E, et al. The potent paracrine effect of umbilical cord mesenchymal stem cells mediates mitochondrial quality control to restore chemotherapy-induced damage in ovarian granulosa cells[J]. Biomed Pharmacother, 2024,172:116263. doi: 10.1016/j.biopha.2024.116263.
[27]	Sun YT, Cai JH, Bao S. Overexpression of lncRNA HCP5 in human umbilical cord mesenchymal stem cell-derived exosomes promoted the proliferation and inhibited the apoptosis of ovarian granulosa cells via the musashi RNA-binding protein 2/oestrogen receptor alpha 1 axis[J]. Endocr J, 2022, 69(9):1117-1129. doi: 10.1507/endocrj.EJ21-0653.
[28]	Gao T, Chen Y, Hu M, et al. MicroRNA-22-3p in human umbilical cord mesenchymal stem cell-secreted exosomes inhibits granulosa cell apoptosis by targeting KLF6 and ATF4-ATF3-CHOP pathway in POF mice[J]. Apoptosis, 2023, 28(7/8):997-1011. doi: 10.1007/s10495-023-01833-5.
[29]	Qu Q, Liu L, Cui Y, et al. miR-126-3p containing exosomes derived from human umbilical cord mesenchymal stem cells promote angiogenesis and attenuate ovarian granulosa cell apoptosis in a preclinical rat model of premature ovarian failure[J]. Stem Cell Res Ther, 2022, 13(1):352. doi: 10.1186/s13287-022-03056-y. pmid: 35883161
[30]	Ren Y, He J, Wang X, et al. Exosomes from adipose-derived stem cells alleviate premature ovarian failure via blockage of autophagy and AMPK/mTOR pathway[J]. PeerJ, 2023,11:e16517. doi: 10.7717/peerj.16517.
[31]	王蕾, 宋春林, 张雨晴, 等. 有丝分裂激酶Aurora B对染色体形态变化的影响[J]. 青岛大学学报(医学版), 2023, 59(1):16-20. doi: 10.11712/jms.2096-5532.2023.59.010.
[32]	Cai JH, Sun YT, Bao S. HucMSCs-exosomes containing miR-21 promoted estrogen production in ovarian granulosa cells via LATS1-mediated phosphorylation of LOXL2 and YAP[J]. Gen Comp Endocrinol, 2022,321-322:114015. doi: 10.1016/j.ygcen.2022.114015.
[33]	时胜洁, 王立光, 高磊, 等. miR-24-3p对猪颗粒细胞雌二醇合成的作用[J]. 畜牧兽医学报, 2024, 55(1):169-178. doi: 10.11843/j.issn.0366-6964.2024.01.017.
[34]	Wang WQ, Chu GH, Hou XX. A comparison of Doppler measures of ovarian blood flow between women with and without ovarian dysfunction and correlations of Doppler indices with ovarian dysfunction markers: a meta-analysis[J]. Ann Transl Med, 2023, 11(2):110. doi: 10.21037/atm-22-5813.
[35]	Xue W, Zhang Q, Chen Y, et al. Hydrogen Sulfide Improves Angiogenesis by Regulating the Transcription of pri-miR-126 in Diabetic Endothelial Cells[J]. Cells, 2022, 11(17):2651. doi: 10.3390/cells11172651.
[36]	Tang M, Tang H, Tu B, et al. SIRT7: a sentinel of genome stability[J]. Open Biol, 2021, 11(6):210047. doi: 10.1098/rsob.210047.
[37]	Ding C, Zhu L, Shen H, et al. Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7[J]. Stem Cells, 2020, 38(9):1137-1148. doi: 10.1002/stem.3204. pmid: 32442343

提取技术		原理	优点	缺点	比较
离心法	①超速离心法	外泌体通过平衡沉降的原理进行分离，根据颗粒大小和密度施加不同的离心力	目前最常用的提取方法，提取到的标本量大，操作简单，费用相对较低	处理时间长，回收率和纯度低。提取出的外泌体对离心机的参数要求较高	a. 外泌体浓度：密度梯度离心法>超速离心法>超滤离心技术 b. 操作时间：密度梯度离心法>超速离心法>超滤离心技术^[16]
	②密度梯度离心法	根据离心力作用下不同沉降系数物质的分层分布分离外泌体	分离效果好，能保存好外泌体的活性，纯度相对较高	准备工作较为繁琐，操作复杂，设备要求高，耗时长，标本量少
	③超滤离心技术^[15]	可以在一定压力下让外泌体通过不同孔径膜的溶质来筛选	提取时间少，过程简单，外泌体回收率较高	外泌体的纯度和浓度较低，一些外泌体也可能黏附在滤膜上，导致产物损失和活性丧失
PEG沉淀法^[17]	PEG沉淀法	PEG与水分子结合后，在低速离心下使大量外泌体凝固沉淀，再用超速离心进行纯化	简单，产量大且外泌体的生物活性不受影响	易产生聚合物，影响数据准确性	与超速离心法相比，外泌体的产量可显著增加
免疫捕获法	①酶联免疫吸附分离法^[18] ②磁珠分离法	抗原抗体特异性吸附	特异性高，操作简单	分离的外泌体难以在后续实验中使用，并且获得的外泌体的活性容易受到影响	-
排阻色谱法^[19]	排阻色谱法	样品通过用凝胶填充的色谱柱，不同直径的粒子以不同的速率洗脱，这样就可以将外泌体与蛋白质、脂质等杂质分离开	操作简单、纯度高，可以保证外泌体的生物活性，适用于下游实验	耗时长，不能用于处理大量样品，色谱不可以重复使用	-

提取技术		原理	优点	缺点	比较
离心法	①超速离心法	外泌体通过平衡沉降的原理进行分离，根据颗粒大小和密度施加不同的离心力	目前最常用的提取方法，提取到的标本量大，操作简单，费用相对较低	处理时间长，回收率和纯度低。提取出的外泌体对离心机的参数要求较高	a. 外泌体浓度：密度梯度离心法>超速离心法>超滤离心技术 b. 操作时间：密度梯度离心法>超速离心法>超滤离心技术^[16]
	②密度梯度离心法	根据离心力作用下不同沉降系数物质的分层分布分离外泌体	分离效果好，能保存好外泌体的活性，纯度相对较高	准备工作较为繁琐，操作复杂，设备要求高，耗时长，标本量少
	③超滤离心技术^[15]	可以在一定压力下让外泌体通过不同孔径膜的溶质来筛选	提取时间少，过程简单，外泌体回收率较高	外泌体的纯度和浓度较低，一些外泌体也可能黏附在滤膜上，导致产物损失和活性丧失
PEG沉淀法^[17]	PEG沉淀法	PEG与水分子结合后，在低速离心下使大量外泌体凝固沉淀，再用超速离心进行纯化	简单，产量大且外泌体的生物活性不受影响	易产生聚合物，影响数据准确性	与超速离心法相比，外泌体的产量可显著增加
免疫捕获法	①酶联免疫吸附分离法^[18] ②磁珠分离法	抗原抗体特异性吸附	特异性高，操作简单	分离的外泌体难以在后续实验中使用，并且获得的外泌体的活性容易受到影响	-
排阻色谱法^[19]	排阻色谱法	样品通过用凝胶填充的色谱柱，不同直径的粒子以不同的速率洗脱，这样就可以将外泌体与蛋白质、脂质等杂质分离开	操作简单、纯度高，可以保证外泌体的生物活性，适用于下游实验	耗时长，不能用于处理大量样品，色谱不可以重复使用	-