外泌体负载的miR-520a-5p对胎鼠宫内生长受限妊娠结局的改善作用及其机制

doi:10.13481/j.1671-587X.20250509

吉林大学学报(医学版) ›› 2025, Vol. 51 ›› Issue (5): 1230-1239.doi: 10.13481/j.1671-587X.20250509

• 基础研究 • 上一篇

外泌体负载的miR-520a-5p对胎鼠宫内生长受限妊娠结局的改善作用及其机制

相萌^1,²(),徐冰³,王培莎²,刘思旗²,张少华³()

^1.西安医学院临床医学院妇产科教研室，陕西西安 710021
^2.西安医学院临床医学院西安肿瘤早诊创新转化重点实验室，陕西西安 710021
^3.西安医学院第一附属医院妇产科，陕西西安 710021

收稿日期:2024-10-30 接受日期:2024-12-19 出版日期:2025-09-28 发布日期:2025-11-05
通讯作者: 相萌,张少华 E-mail:xjtuxm@126.com;zhangshaohua72@163.com
作者简介:相萌（1983-），女，陕西省西安市人，副教授，医学博士，主要从事妇产科学基础和临床方面的研究。
基金资助:
陕西省科技厅自然科学基础研究计划项目(2022JQ-804);陕西省西安市科技局医学研究一般项目(24YXYJ0197)

Effect of exosomes loaded with miR-520a-5p on pregnancy outcomes in fetal mice with intrauterine growth restriction and its mechanism

Meng XIANG^1,²(),Bing XU³,Peisha WANG²,Siqi LIU²,Shaohua ZHANG³()

^1.Department of Obstetrics and Gynecology，School of Clinical Medicine，Xi’an Medical University，Xi’an 710021，China
^2.Xi’an Key Laboratory for Innovative Translation of Early Cancer Diagnosis，School of Clinical Medicine，Xi’an Medical University，Xi’an 710021，China
^3.Department of Obstetrics and Gynecology，First Affiliated Hospital，Xi’an Medical University，Xi’an 710021，China

Received:2024-10-30 Accepted:2024-12-19 Online:2025-09-28 Published:2025-11-05
Contact: Meng XIANG,Shaohua ZHANG E-mail:xjtuxm@126.com;zhangshaohua72@163.com

摘要/Abstract

摘要：

目的探讨外泌体（Exos）负载的微小RNA-520a-5p（miR-520a-5p）对胎鼠宫内生长受限（FGR）妊娠结局的影响，并阐明其作用机制。方法体外培养小鼠胎盘间充质干细胞（MSCs），并利用miR-520a-5p腺病毒载体（Ad-miR-520a-5p）转染获得高负载miR-520a-5p的Exos（miR-520a-5p-MSCs-Exos）并进行鉴定。C57BL/6小鼠按照雌雄2∶1的比例合笼交配成功妊娠，将40只怀孕小鼠分为对照组、FGR组、NC-MSCs-Exos组和miR-520a-5p-MSCs-Exos组，每组10只。除对照组外，其余组小鼠采用孕期过度暴露地塞米松（DEX）诱发妊娠期母体小鼠的FGR模型。检测胎鼠出生体质量和生后1、2、3及4周体质量，采用实时荧光定量PCR（RT-qPCR）法检测各组小鼠胎盘组织中miR-520a-5p、DNA甲基转移酶3b（DNMT3b）和血管内皮生长因子（VEGF）mRNA表达水平，Western blotting法检测各组小鼠胎盘组织中DNMT3b和VEGF蛋白表达水平，甲基化特异性PCR（MSP）分析各组小鼠胎盘组织中VEGF启动子甲基化率，双荧光素酶报告基因实验验证miR-520a-5p与DNMT3b之间的靶向关系。结果透射电子显微镜（TEM）和纳米粒子追踪分析（NTA）分析，Exos呈球形，粒径集中在100 nm附近；Western blotting法，Exos表面生物标志物CD63和CD81均呈阳性表达；RT-qPCR法，与NC-MSCs-Exos和Ad-NC-MSCs-Exos比较，Ad-miR-520a-5p-MSCs-Exos中miR-520a-5p表达水平升高（P<0.001）。4组子代小鼠出生体质量和生后1、2及3周体质量比较差异均有统计学意义（F=36.084，F=19.851，F=77.755，F=103.223；P<0.001）。与对照组比较，FGR组子代小鼠出生体质量和生后1、2及3周体质量均降低（P<0.05）；与FGR组和NC-MSCs-Exos组比较，miR-520a-5p-MSCs-Exos组子代小鼠出生体质量和生后1、2及3周体质量均升高（P<0.05）。单因素方差分析，4组小鼠胎盘组织中miR-520a-5p、DNMT3b和VEGF mRNA表达水平比较差异有统计学意义（F=103.224，F=856.460，F=214.563；P<0.001）；组间两两比较，与对照组比较，FGR组小鼠胎盘组织中miR-520a-5p和VEGF mRNA表达水平降低（P<0.05），DNMT3b mRNA表达水平升高（P<0.05）；与FGR组和NC-MSCs-Exos组比较，miR-520a-5p-MSCs-Exos组小鼠胎盘组织中miR-520a-5p和VEGF mRNA表达水平升高（P<0.05），DNMT3b mRNA表达水平降低（P<0.05）。单因素方差分析，4组小鼠胎盘组织中DNMT3b和VEGF蛋白表达水平比较差异有统计学意义（F=245.601，F=149.360；P<0.001）；组间两两比较，与对照组比较，FGR组小鼠胎盘组织中DNMT3b蛋白水平升高（P<0.05），VEGF蛋白表达水平降低（P<0.05）；与FGR组和NC-MSCs-Exos组比较，miR-520a-5p-MSCs-Exos组小鼠胎盘组织中DNMT3b蛋白表达水平降低（P<0.05），VEGF蛋白表达水平升高（P<0.05）。单因素方差分析，4组小鼠胎盘组织中VEGF启动子甲基化率比较差异有统计学意义（F=687.096，P<0.001）；组间两两比较，与对照组比较，FGR组小鼠胎盘组织中VEGF启动子甲基化率升高（P<0.05）；与FGR组和NC-MSCs-Exos组比较，miR-520a-5p-MSCs-Exos组小鼠胎盘组织中VEGF启动子甲基化率降低（P<0.05）。双荧光素酶报告基因实验，与miR-NC组比较，miR-520a-5p组DNMT3b-WT报告载体细胞的荧光素酶活性明显降低（P<0.05）；与miR-NC组比较，miR-520a-5p组DNMT3b-MUT报告载体细胞的荧光素酶活性无明显改变，差异无统计学意义（P>0.05）。结论高负载miR-520a-5p的MSCs来源的Exos可能通过靶向下调DNMT3b表达，抑制VEGF甲基化，促进VEGF表达，改善FGR胎鼠妊娠结局。

关键词: 胎儿宫内生长受限, 外泌体, 间充质干细胞, 微小RNA-520a-5p, DNA甲基转移酶3b, 血管内皮生长因子

Abstract:

Objective To discuss the effect of exosomes （Exos） loaded with microRNA-520a-5p（miR-520a-5p） on the pregnancy outcomes in fetal mice with intrauterine growth restriction （FGR）， and to clarify its mechanism. Methods The mouse placental mesenchymal stem cells （MSCs） were cultured in vitro and transfected with miR-520a-5p adenovirus vector （Ad-miR-520a-5p） to obtain the Exos with high miR-520a-5p load （miR-520a-5p-MSCs-Exos）， which were then identified. The C57BL/6 mice were mated in cages at a female∶male ratio of 2∶1 to achieve successful pregnancy. Forty pregnant mice were divided into control group， FGR group， NC-MSCs-Exos group， and miR-520a-5p-MSCs-Exos group， with 10 mice in each group. Except for control group， the mice in other groups were exposed to excessive dexamethasone （DEX） during pregnancy to induce FGR models in the pregnant mice. The body weights of the fetal mice at birth and at 1， 2， 3， and 4 weeks after birth were detected； real-time fluorescence quantitative PCR （RT-qPCR） method was used to detect the expression levels of miR-520a-5p， DNA methyltransferase 3b（DNMT3b）， and vascular endothelial growth factor（VEGF） mRNA in placenta tissue of the mice in various groups； Western blotting method was used to detect the expression levels of DNMT3b and VEGF proteins in placenta tissue of the mice in various groups； methylation-specific PCR （MSP） was used to analyze the methylation rates of VEGF promoter in placenta tissue of the mice in various groups； dual-luciferase reporter gene assay was used to verify the targeting relationship between miR-520a-5p and DNMT3b. Results The results of transmission electron microscope（TEM） and nanoparticle tracking analysis（NTA） showed that the Exos were spherical with particle size concentrated near 100 nm； the Western blotting method results showed that the surface biomarkers CD63 and CD81 of Exos were positively expressed. The RT-qPCR results showed that compared with NC-MSCs-Exos and Ad-NC-MSCs-Exos， the expression level of miR-520a-5p in Ad-miR-520a-5p-MSCs-Exos was increased （P<0.001）. The differences in birth body weight and the body weights at 1， 2， and 3 weeks after birth of the fetal mice among four groups were statistically significant （F=36.084， F=19.851， F=77.755， F=103.223； P<0.001）. Compared with control group， the birth body weight and the body weights at 1， 2， and 3 weeks after birth of the fetal mice in FGR group were decreased （P<0.05）； compared with FGR group and NC-MSCs-Exos group， the birth body weight and the body weights at 1， 2， and 3 weeks after birth of the fetal mice in miR-520a-5p-MSCs-Exos group were increased （P<0.05）. The One-way ANOVA results showed that the differences in the expression levels of miR-520a-5p， DNMT3b， and VEGF mRNA in placenta tissue of the mice among four groups were statistically significant （F=103.224， F=856.460， F=214.563； P<0.001）. The pairwise comparison between groups showed that compared with control group， the expression levels of miR-520a-5p and VEGF mRNA in placenta tissue of the mice in FGR group were decreased （P<0.05）， and the expression level of DNMT3b mRNA was increased （P<0.05）； compared with FGR group and NC-MSCs-Exos group， the expression levels of miR-520a-5p and VEGF mRNA in placenta tissue of the mice in miR-520a-5p-MSCs-Exos group were increased （P<0.05）， and the expression level of DNMT3b mRNA was decreased （P<0.05）. The One-way ANOVA results showed that the differences in the expression levels of DNMT3b and VEGF proteins in placenta tissue of the mice among four groups were statistically significant （F=245.601， F=149.360； P<0.001）. The pairwise comparison between groups showed that compared with control group， the expression level of DNMT3b protein in placenta tissue of the mice in FGR group was increased （P<0.05）， and the expression level of VEGF protein was decreased （P<0.05）； compared with FGR group and NC-MSCs-Exos group， the expression level of DNMT3b protein in placenta tissue of the mice in miR-520a-5p-MSCs-Exos group was decreased （P<0.05）， and the expression level of VEGF protein was increased （P<0.05）. The One-way ANOVA results showed that the difference in the methylation rate of VEGF promoter in placenta tissue of the mice among four groups was statistically significant （F=687.096， P<0.001）. The pairwise comparison between groups showed that compared with control group， the methylation rate of VEGF promoter in placenta tissue of the mice in FGR group was increased （P<0.05）； compared with FGR group and NC-MSCs-Exos group， the methylation rate of VEGF promoter in placenta tissue of the mice in miR-520a-5p-MSCs-Exos group was decreased （P<0.05）. Dual-luciferase reporter gene assay results showed that compared with miR-NC group， the luciferase activity in the cells containing DNMT3b-WT reporter vector in miR-520a-5p group was decreased （P<0.05）； compared with miR-NC group， the luciferase activity in the cells containing DNMT3b-MUT reporter vector in miR-520a-5p group had no change， no significant difference was observed （P>0.05）. Conclusion The MSCs-derived Exos highly loaded with miR-520a-5p may improve the pregnancy outcomes of FGR fetal mice by targeting and down-regulating the expression of DNMT3b， inhibiting VEGF methylation， and promoting VEGF expression.

Key words: Fetal growth restriction, Exosome, Mesenchymal stem cell, MicroRNA-520a-5p, DNA methyltransferase 3b, Vascular endothelial growth factor

中图分类号:

R715.5

相萌,徐冰,王培莎,刘思旗,张少华. 外泌体负载的miR-520a-5p对胎鼠宫内生长受限妊娠结局的改善作用及其机制[J]. 吉林大学学报(医学版), 2025, 51(5): 1230-1239.

Meng XIANG,Bing XU,Peisha WANG,Siqi LIU,Shaohua ZHANG. Effect of exosomes loaded with miR-520a-5p on pregnancy outcomes in fetal mice with intrauterine growth restriction and its mechanism[J]. Journal of Jilin University(Medicine Edition), 2025, 51(5): 1230-1239.

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Primer	Sequence （5'-3'）
MiR-520a-5p	Forward：TCGGCAGGCUCCAGAGGGAAGU
	Reverse：CACTCAACTGGTGTCGTGGA
DNMT3b	Forward：AGGGAAGACTCGATCCTCGTC
	Reverse：GTGTGTAGCTTAGCAGACTGG
VEGF	Forward：GCAGGCTGCTGTAACGATGA
	Reverse：GCATGATCTGCATGGTGATGTT
U6	Forward：CTCGCTTCGGCAGCACA
	Reverse：AACGCTTCACGAATTTGCGT
β-actin	Forward：GGCATCCTCACCCTGAAGTA
	Reverse：TAGCACAGCCTGGATAGCAA

Group	Body weight
Group	Birth	1 week	2 week	3 week	4 week
Control	1.41±0.12	5.15±0.23	9.26±0.25	13.38±0.31	17.05±0.36
FGR	1.03±0.08^*	4.58±0.17^*	8.01±0.22^*	11.52±0.27^*	16.84±0.41
NC-MSCs-Exos	1.01±0.09	4.53±0.20	7.94±0.21	11.47±0.29	16.76±0.39
MiR-520a-5p-MSCs-Exos	1.22±0.10^△#	4.90±0.22^△#	8.83±0.24^△#	12.79±0.31^△#	17.02±0.40

Group	miR-520a-5p	DNMT3b	VEGF
Control	1.00±0.11	1.03±0.14	1.01±0.10
FGR	0.48±0.07^*	4.32±0.22^*	0.32±0.05^*
NC-MSCs-Exos	0.45±0.06	4.38±0.20	0.30±0.06
MiR-520a-5p- MSCs-Exos	0.89±0.10^△#	2.07±0.15^△#	0.76±0.08^△#

外泌体负载的miR-520a-5p对胎鼠宫内生长受限妊娠结局的改善作用及其机制

Effect of exosomes loaded with miR-520a-5p on pregnancy outcomes in fetal mice with intrauterine growth restriction and its mechanism

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