• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

由人脐带间充质干细胞衍生的携带簇集蛋白的细胞外囊泡通过激活 PI3K/AKT 通路恢复卵巢早衰小鼠的卵巢功能。

Clusterin-carrying extracellular vesicles derived from human umbilical cord mesenchymal stem cells restore the ovarian function of premature ovarian failure mice through activating the PI3K/AKT pathway.

机构信息

Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.

College of Life Sciences, Hubei University, Wuhan, China.

出版信息

Stem Cell Res Ther. 2024 Sep 13;15(1):300. doi: 10.1186/s13287-024-03926-7.

DOI:10.1186/s13287-024-03926-7
PMID:39272156
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11401318/
Abstract

BACKGROUND

Emerging evidence has highlighted the therapeutic potential of human umbilical cord mesenchymal stem cells (UC-MSCs) in chemotherapy-induced premature ovarian failure (POF). This study was designed to investigate the appropriate timing and molecular mechanism of UC-MSCs treatment for chemotherapy-induced POF.

METHODS

Ovarian structure and function of mice were assessed every 3 days after injections with cyclophosphamide (CTX) and busulfan (BUS). UC-MSCs and UC-MSCs-derived extracellular vesicles (EVs) were infused into mice via the tail vein, respectively. Ovarian function was analyzed by follicle counts, the serum levels of hormones and ovarian morphology. The apoptosis and proliferation of ovarian granulosa cells were analyzed in vitro and in vivo. Label-free quantitative proteomics was used to detect the differentially expressed proteins in UC-MSC-derived EVs.

RESULTS

After CTX/BUS injection, we observed that the ovarian function of POF mice was significantly deteriorated on day 9 after CTX/BUS infusion. TUNEL assay indicated that the number of apoptotic cells in the ovaries of POF mice was significantly higher than that in normal mice on day 3 after CTX/BUS injection. Transplantation of UC-MSCs on day 6 after CTX/BUS injection significantly improved ovarian function, enhanced proliferation and inhibited apoptosis of ovarian granulosa cells, whereas the therapeutic effect of UC-MSCs transplantation decreased on day 9, or day 12 after CTX/BUS injection. Moreover, EVs derived from UC-MSCs exerted similar therapeutic effects on POF. UC-MSCs-derived EVs could activate the PI3K/AKT signaling pathway and reduce ovarian granulosa cell apoptosis. Quantitative proteomics analysis revealed that clusterin (CLU) was highly expressed in the EVs of UC-MSCs. The supplementation of CLU proteins prevented ovarian granulosa cells from chemotherapy-induced apoptosis. Further mechanistic analysis showed that CLU-knockdown blocked the PI3K/AKT signaling and reversed the protective effects of UC-MSCs-derived EVs.

CONCLUSIONS

Administration of UC-MSCs and UC-MSCs-derived EVs on day 6 of CTX/BUS injection could effectively improve the ovarian function of POF mice. UC-MSCs-derived EVs carrying CLU promoted proliferation and inhibited apoptosis of ovarian granulosa cells through activating the PI3K/AKT pathway. This study identifies a previously unrecognized molecular mechanism of UC-MSCs-mediated protective effects on POF, which pave the way for the use of cell-free therapeutic approach for POF.

摘要

背景

新出现的证据强调了人脐带间充质干细胞（UC-MSCs）在化疗诱导的卵巢早衰（POF）中的治疗潜力。本研究旨在探讨 UC-MSCs 治疗化疗诱导的 POF 的适宜时机和分子机制。

方法

在给予环磷酰胺（CTX）和白消安（BUS）后，每隔 3 天评估小鼠的卵巢结构和功能。分别通过尾静脉输注 UC-MSCs 和 UC-MSCs 衍生的细胞外囊泡（EVs）。通过卵泡计数、血清激素水平和卵巢形态分析卵巢功能。在体外和体内分析卵巢颗粒细胞的凋亡和增殖。使用无标记定量蛋白质组学检测 UC-MSC 衍生 EVs 中的差异表达蛋白。

结果

CTX/BUS 注射后，我们观察到 POF 小鼠的卵巢功能在 CTX/BUS 输注后第 9 天明显恶化。TUNEL 检测表明，CTX/BUS 注射后第 3 天 POF 小鼠卵巢中凋亡细胞的数量明显高于正常小鼠。CTX/BUS 注射后第 6 天移植 UC-MSCs 可显著改善卵巢功能，增强卵巢颗粒细胞的增殖并抑制其凋亡，而 CTX/BUS 注射后第 9 天或第 12 天移植 UC-MSCs 的治疗效果降低。此外，UC-MSCs 衍生的 EVs 对 POF 具有相似的治疗作用。UC-MSCs 衍生的 EVs 可激活 PI3K/AKT 信号通路并减少卵巢颗粒细胞凋亡。定量蛋白质组学分析显示，CLU 在 UC-MSCs 的 EVs 中高表达。CLU 蛋白的补充可防止卵巢颗粒细胞发生化疗诱导的凋亡。进一步的机制分析表明，CLU 敲低阻断了 PI3K/AKT 信号通路并逆转了 UC-MSCs 衍生 EVs 的保护作用。

结论

CTX/BUS 注射后第 6 天给予 UC-MSCs 和 UC-MSCs 衍生的 EVs 可有效改善 POF 小鼠的卵巢功能。UC-MSCs 衍生的携带 CLU 的 EVs 通过激活 PI3K/AKT 通路促进卵巢颗粒细胞增殖并抑制其凋亡。本研究确定了 UC-MSCs 介导的对 POF 的保护作用的一个以前未被认识的分子机制，为 POF 的无细胞治疗方法的应用铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/970c99dc84c8/13287_2024_3926_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/f008a0ca09bd/13287_2024_3926_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/a8a6db5f761a/13287_2024_3926_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/b1c9803dd8b4/13287_2024_3926_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/2c7782ca1322/13287_2024_3926_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/271361eeabbc/13287_2024_3926_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/5d5181c225b9/13287_2024_3926_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/b2e9428502cc/13287_2024_3926_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/f0fc15899ae2/13287_2024_3926_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/649ca70e3799/13287_2024_3926_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/970c99dc84c8/13287_2024_3926_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/f008a0ca09bd/13287_2024_3926_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/a8a6db5f761a/13287_2024_3926_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/b1c9803dd8b4/13287_2024_3926_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/2c7782ca1322/13287_2024_3926_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/271361eeabbc/13287_2024_3926_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/5d5181c225b9/13287_2024_3926_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/b2e9428502cc/13287_2024_3926_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/f0fc15899ae2/13287_2024_3926_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/649ca70e3799/13287_2024_3926_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8772/11401318/970c99dc84c8/13287_2024_3926_Fig10_HTML.jpg

相似文献

1
Clusterin-carrying extracellular vesicles derived from human umbilical cord mesenchymal stem cells restore the ovarian function of premature ovarian failure mice through activating the PI3K/AKT pathway.由人脐带间充质干细胞衍生的携带簇集蛋白的细胞外囊泡通过激活 PI3K/AKT 通路恢复卵巢早衰小鼠的卵巢功能。
Stem Cell Res Ther. 2024 Sep 13;15(1):300. doi: 10.1186/s13287-024-03926-7.
2
Human Umbilical Cord Mesenchymal Stem Cells Improve Ovarian Function in Chemotherapy-Induced Premature Ovarian Failure Mice Through Inhibiting Apoptosis and Inflammation via a Paracrine Mechanism.人脐带间充质干细胞通过旁分泌机制抑制细胞凋亡和炎症，改善化疗诱导的卵巢早衰小鼠的卵巢功能。
Reprod Sci. 2021 Jun;28(6):1718-1732. doi: 10.1007/s43032-021-00499-1. Epub 2021 Mar 9.
3
Therapeutic effects of human umbilical cord mesenchymal stem cell-derived extracellular vesicles on ovarian functions through the PI3K/Akt cascade in mice with premature ovarian failure.人脐带间充质干细胞来源的细胞外囊泡通过 PI3K/Akt 级联对卵巢早衰小鼠卵巢功能的治疗作用。
Eur J Histochem. 2023 Jul 27;67(3):3506. doi: 10.4081/ejh.2023.3506.
4
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model.人脐带间充质干细胞（hUC-MSCs）通过 VEGFA/PI3K/AKT/mTOR 通路减轻卵巢早衰大鼠模型中卵巢颗粒细胞的过度自噬。
J Ovarian Res. 2023 Sep 30;16(1):198. doi: 10.1186/s13048-023-01278-z.
5
Regenerative potential of different extracellular vesicle subpopulations derived from clonal mesenchymal stem cells in a mouse model of chemotherapy-induced premature ovarian failure.化疗诱导的小鼠卵巢早衰模型中克隆间充质干细胞来源的不同细胞外囊泡亚群的再生潜力
Life Sci. 2023 May 15;321:121536. doi: 10.1016/j.lfs.2023.121536. Epub 2023 Mar 1.
6
Small extracellular vesicles derived from embryonic stem cells restore ovarian function of premature ovarian failure through PI3K/AKT signaling pathway.来源于胚胎干细胞的小细胞外囊泡通过 PI3K/AKT 信号通路恢复卵巢早衰的卵巢功能。
Stem Cell Res Ther. 2020 Jan 3;11(1):3. doi: 10.1186/s13287-019-1508-2.
7
Effects of single and multiple transplantations of human umbilical cord mesenchymal stem cells on the recovery of ovarian function in the treatment of premature ovarian failure in mice.单次和多次移植人脐带间充质干细胞对治疗小鼠卵巢早衰中卵巢功能恢复的影响。
J Ovarian Res. 2021 Sep 15;14(1):119. doi: 10.1186/s13048-021-00871-4.
8
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.来源于人脐带间充质干细胞的含有 miR-126-3p 的外泌体可促进血管生成并减轻早发性卵巢功能衰竭的临床前大鼠模型中的卵巢颗粒细胞凋亡。
Stem Cell Res Ther. 2022 Jul 26;13(1):352. doi: 10.1186/s13287-022-03056-y.
9
Intraovarian injection of 3D-MSC-EVs-ECM gel significantly improved rat ovarian function after chemotherapy.三维 MSC-EVs-ECM 凝胶经卵巢内注射后，可显著改善化疗后大鼠的卵巢功能。
Reprod Biol Endocrinol. 2024 Oct 16;22(1):125. doi: 10.1186/s12958-024-01299-3.
10
Extracellular Vesicles Derived from Mesenchymal Stem Cells Recover Fertility of Premature Ovarian Insufficiency Mice and the Effects on their Offspring.间充质干细胞来源的细胞外囊泡恢复卵巢早衰小鼠的生育能力及其对子代的影响。
Cell Transplant. 2020 Jan-Dec;29:963689720923575. doi: 10.1177/0963689720923575.

引用本文的文献

1
Extracellular vesicle-based drug overview: research landscape, quality control and nonclinical evaluation strategies.基于细胞外囊泡的药物概述：研究现状、质量控制及非临床评估策略
Signal Transduct Target Ther. 2025 Aug 14;10(1):255. doi: 10.1038/s41392-025-02312-w.
2
Extracellular vesicle-enriched secretome of adipose-derived stem cells upregulates clusterin to alleviate doxorubicin-induced apoptosis in cardiomyocytes.脂肪来源干细胞富含细胞外囊泡的分泌组上调簇集蛋白以减轻阿霉素诱导的心肌细胞凋亡。
Biol Direct. 2025 Jul 16;20(1):84. doi: 10.1186/s13062-025-00664-5.
3
Precision medicine in premature ovarian insufficiency: a focus on the precision therapeutic strategies for mesenchymal stem cells.

本文引用的文献

1
Follicular reconstruction and neo-oogenesis in xenotransplantation of human ovarian isolated cells derived from chemotherapy-induced POF patients.化疗诱导的卵巢早衰患者来源的人卵巢分离细胞异种移植中的卵泡重建和新卵泡生成
J Biol Eng. 2023 Nov 20;17(1):70. doi: 10.1186/s13036-023-00384-2.
2
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model.人脐带间充质干细胞（hUC-MSCs）通过 VEGFA/PI3K/AKT/mTOR 通路减轻卵巢早衰大鼠模型中卵巢颗粒细胞的过度自噬。
J Ovarian Res. 2023 Sep 30;16(1):198. doi: 10.1186/s13048-023-01278-z.
3
精准医学在卵巢早衰中的应用：聚焦间充质干细胞的精准治疗策略
Stem Cell Res Ther. 2025 Jul 16;16(1):381. doi: 10.1186/s13287-025-04512-1.
4
The role and mechanism of mesenchymal stem cells in immunomodulation of type 1 diabetes mellitus and its complications: recent research progress and challenges: a review.间充质干细胞在1型糖尿病及其并发症免疫调节中的作用和机制：最新研究进展与挑战：综述
Stem Cell Res Ther. 2025 Jun 17;16(1):308. doi: 10.1186/s13287-025-04431-1.
5
Exosomes derived from a mesenchymal-like endometrial regenerative cells ameliorate renal ischemia reperfusion injury through delivery of CD73.源自间充质样子宫内膜再生细胞的外泌体通过递送CD73改善肾缺血再灌注损伤。
Stem Cell Res Ther. 2025 Mar 26;16(1):148. doi: 10.1186/s13287-025-04275-9.
6
Ovarian Mechanobiology: Understanding the Interplay Between Mechanics and Follicular Development.卵巢力学生物学：理解力学与卵泡发育之间的相互作用
Cells. 2025 Feb 28;14(5):355. doi: 10.3390/cells14050355.
Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence.
脂肪源干细胞通过抑制颗粒细胞凋亡和衰老促进化疗诱导的卵巢早衰的修复。
Stem Cell Res Ther. 2023 Apr 11;14(1):75. doi: 10.1186/s13287-023-03297-5.
4
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.人脐带间充质干细胞分泌的外泌体中的 microRNA-22-3p 通过靶向 KLF6 和 ATF4-ATF3-CHOP 通路抑制 POF 小鼠颗粒细胞凋亡。
Apoptosis. 2023 Aug;28(7-8):997-1011. doi: 10.1007/s10495-023-01833-5. Epub 2023 Mar 31.
5
Regenerative potential of different extracellular vesicle subpopulations derived from clonal mesenchymal stem cells in a mouse model of chemotherapy-induced premature ovarian failure.化疗诱导的小鼠卵巢早衰模型中克隆间充质干细胞来源的不同细胞外囊泡亚群的再生潜力
Life Sci. 2023 May 15;321:121536. doi: 10.1016/j.lfs.2023.121536. Epub 2023 Mar 1.
6
Intraovarian Administration of Autologous Menstrual Blood Derived-Mesenchymal Stromal Cells in Women with Premature Ovarian Failure.对卵巢早衰女性进行自体月经血源性间充质基质细胞的卵巢内给药。
Arch Med Res. 2023 Feb;54(2):135-144. doi: 10.1016/j.arcmed.2022.12.015. Epub 2023 Jan 25.
7
Medical Grade Honey as a Promising Treatment to Improve Ovarian Tissue Transplantation.医用级蜂蜜作为改善卵巢组织移植的一种有前景的治疗方法。
Bioengineering (Basel). 2022 Jul 30;9(8):357. doi: 10.3390/bioengineering9080357.
8
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.来源于人脐带间充质干细胞的含有 miR-126-3p 的外泌体可促进血管生成并减轻早发性卵巢功能衰竭的临床前大鼠模型中的卵巢颗粒细胞凋亡。
Stem Cell Res Ther. 2022 Jul 26;13(1):352. doi: 10.1186/s13287-022-03056-y.
9
Clusterin exacerbates interleukin-1β-induced inflammation via suppressing PI3K/Akt pathway in human fibroblast-like synoviocytes of knee osteoarthritis.簇集蛋白通过抑制 PI3K/Akt 通路加重膝骨关节炎人成纤维样滑膜细胞中白细胞介素-1β诱导的炎症。
Sci Rep. 2022 Jun 15;12(1):9963. doi: 10.1038/s41598-022-14295-7.
10
Hsa_circ_0063804 enhances ovarian cancer cells proliferation and resistance to cisplatin by targeting miR-1276/CLU axis.Hsa_circ_0063804 通过靶向 miR-1276/CLU 轴促进卵巢癌细胞增殖和对顺铂的耐药性。
Aging (Albany NY). 2022 Jun 10;14(11):4699-4713. doi: 10.18632/aging.203474.