Abstract
Research question
What is the specific mechanism of umbilical cord mesenchymal stem cell-derived exosomes
(UCMSC-exos) in regulating endometrial repair and regeneration?
Design
In this study, UCMSC-exos were harvested by differential ultracentrifugation from
umbilical cord mesenchymal stem cell culture supernatant and identified with western
blotting, transmission electron microscopy and nanoparticle tracking analysis. Transforming
growth factor-β1 (TGFβ1) at different concentrations was used to construct the intrauterine
adhesions cell model. The fibrotic markers were assessed by quantitative reverse transcription-polymerase
chain reaction and western blotting. The effects of miR-145-5p over-expression on
endometrial fibrosis were assessed. Dual luciferase assay was performed to verify
the relationship between miR-145-5p and zinc finger E-box binding homeobox 2 (ZEB2).
Results
The isolated UCMSC-exos had a typical cup-shaped morphology, expressed the specific
exosomal markers Alix, CD63 and TSG101, and were approximately 50–150 nm in diameter.
TGFβ1 at 10 ng/ml significantly promoted endometrial fibrosis, which was reversed
by 20 µg/ml UCMSC-exos. Exosomal miR-145-5p ameliorated TGFβ1-induced endometrial
fibrosis. ZEB2 was inversely regulated by exosomal miR-145-5p as a direct target.
Conclusions
UCMSC-exos might reverse endometrial stromal cell fibrosis by regulating the miR-145-5p/ZEB2
axis, representing a potential novel strategy to promote endometrial repair.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Reproductive BioMedicine OnlineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- AAGL Practice Report: Practice Guidelines on Intrauterine Adhesions Developed in Collaboration With the European Society of Gynaecological Endoscopy (ESGE).J. Minim. Invasive Gynecol. 2017; 24: 695-705
- Human umbilical cord mesenchymal stem cell-derived extracellular vesicles: a novel therapeutic paradigm.J. Cell. Physiol. 2020; 235: 706-717
- Exosome-delivered microRNAs modulate the inflammatory response to endotoxin.Nat. Commun. 2015; 6: 7321
- Comparison of human mesenchymal stromal cells from four neonatal tissues: amniotic membrane, chorionic membrane, placental decidua and umbilical cord.Cytotherapy. 2017; 19: 577-585
- GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues.Physiol. Genomics. 2005; 21: 389-395
- MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297
- Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial.Stem. Cell. Res. Ther. 2018; 9: 192
- Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction.Cardiovasc. Res. 2018; 114: 1029-1040
- Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis.Theranostics. 2018; 8: 1399-1410
- MicroRNA-545 targets ZEB2 to inhibit the development of non-small cell lung cancer by inactivating Wnt/beta-catenin pathway.Oncol. Lett. 2019; 18: 2931-2938
- miR-145 attenuates cardiac fibrosis through the AKT/GSK-3β/β-catenin signaling pathway by directly targeting SOX9 in fibroblasts.J. Cell. Biochem. 2021; 122: 209-221
- Exosomes derived from human umbilical cord mesenchymal stromal cells deliver exogenous miR-145–5p to inhibit pancreatic ductal adenocarcinoma progression.Cancer Lett. 2019; 442: 351-361
- Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317
- U6 can be used as a housekeeping gene for urinary sediment miRNA studies of IgA nephropathy.Sci. Rep. 2018; 8: 10875
- Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model.Stem. Cell. Res. Ther. 2018; 9: 175
- Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation.Kidney Int. 2017; 92: 114-124
- Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing.Stem. Cells Transl. Med. 2016; 5: 1425-1439
- Bone marrow mesenchymal stem cells (BMSCs) restore functional endometrium in the rat model for severe Asherman syndrome.Reprod. Sci. 2019; 26: 436-444
- Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice.Stem. Cells Transl. Med. 2017; 6: 1262-1272
- The role of the TGF-β superfamily in myocardial infarction.Front Cardiovasc. Med. 2019; 6: 140
- Hysteroscopic management of Asherman's syndrome.J. Minim. Invasive Gynecol. 2018; 25: 218-228
- Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.Stem. Cell. Res. Ther. 2018; 9: 17
- CpG island hypermethylation-associated silencing of microRNAs promotes human endometrial cancer.Cancer Cell. Int. 2013; 13: 44
- miR-200c suppresses endometriosis by targeting MALAT1 in vitro and in vivo.Stem. Cell. Res. Ther. 2017; 8: 251
- Transforming growth factor beta (TGF-beta) isoforms in wound healing and fibrosis.Wound Repair Regen. 2016; 24: 215-222
- Impact of microRNA regulation on variation in human gene expression.Genome Res. 2012; 22: 1243-1254
- Exosomes derived from human umbilical cord mesenchymal stem cells promote proliferation of allogeneic endometrial stromal cells.Reprod. Sci. 2020; 27: 1372-1381
- Isolation, cultivation, and characterization of human mesenchymal stem cells.Cytometry A. 2018; 93: 19-31
- Mesenchymal-to-epithelial transition contributes to endometrial regeneration following natural and artificial decidualization.Stem. Cells. Dev. 2013; 22: 964-974
- Exosomes.Annu. Rev. Biochem. 2019; 88: 487-514
- Human mesenchymal stromal cell-derived extracellular vesicles modify microglial response and improve clinical outcomes in experimental spinal cord injury.Sci. Rep. 2018; 8: 480
- A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options.Curr. Opin. Obstet. Gynecol. 2017; 29: 249-256
- Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast.Cell. 2011; 145: 926-940
- An exosomal urinary miRNA signature for early diagnosis of renal fibrosis in lupus nephritis.Cells. 2019; 8: 773
- Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147.FASEB J. 2018; 32: 6038-6050
- Transforming growth factor-β signalling in renal fibrosis: from Smads to non-coding RNAs.J. Physiol. 2018; 596: 3493-3503
- miRNA-146a improves immunomodulatory effects of MSC-derived exosomes in rheumatoid arthritis.Curr. Gene. Ther. 2020; 20: 297-312
- Human serum enhances the proliferative capacity and immunomodulatory property of MSCs derived from human placenta and umbilical cord.Stem. Cell. Res. Ther. 2019; 10: 79
- Isolation and characterization of exosomes from cell culture supernatants and biological fluids.Curr. Protoc. Cell. Biol. 2006; Chapter 3: 3-22
- Shedding light on the cell biology of extracellular vesicles.Nat. Rev. Mol. Cell. Biol. 2018; 19: 213-228
- The role of the ZEB family of transcription factors in development and disease.Cell. Mol. Life Sci. 2009; 66: 773-787
- SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5’-CACCT sequences in candidate target genes.J. Biol. Chem. 1999; 274: 20489-20498
- Exosomes derived from umbilical cord mesenchymal stem cells alleviate mifepristone-induced human endometrial stromal cell injury.Stem. Cells Int. 2020; 2020: 1-9
- Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications.J. Extracell Vesicles. 2019; 81609206
- Exosomal transfer of bone marrow mesenchymal stem cell-derived miR-340 attenuates endometrial fibrosis.Biol. Open. 2019; 8bio039958
- MiR-145: a potential biomarker of cancer migration and invasion.Am. J. Transl. Res. 2019; 11: 6739-6753
- Mesenchymal stem-cell-derived exosomal miR-145 inhibits atherosclerosis by targeting JAM-A.Mol. Ther. Nucleic Acids. 2021; 23: 119-131
- Mesenchymal stem cells derived from Wharton jelly of the human umbilical cord ameliorate damage to human endometrial stromal cells.Fertil. Steril. 2011; 96: 1029-1036
- CD34(+) KLF4(+) stromal stem cells contribute to endometrial regeneration and repair.Cell. Rep. 2019; 27: 2709-2724
- Asherman syndrome – one century later.Fertil. Steril. 2008; 89: 759-779
- Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase.Stem. Cell. Res. Ther. 2018; 9: 36
- MiR-20a-containing exosomes from umbilical cord mesenchymal stem cells alleviates liver ischemia/reperfusion injury.J. Cell. Physiol. 2020; 235: 3698-3710
- Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration.Osteoarthritis Cartilage. 2016; 24: 2135-2140
- MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway.Mol. Immunol. 2016; 75: 151-160
Biography
Xiao Li is a master's student at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Her research interests include clinical diagnosis and treatment and the basic research of uterine diseases.
Key message
Intrauterine adhesions are a kind of endometrial injury disease, and the pathological manifestations are mainly endometrial fibrosis. Umbilical cord mesenchymal stem cell-derived exosomes may reverse endometrial stromal cell fibrosis by regulating the miR-145-5p/ZEB2 axis, representing a potential strategy to promote endometrial repair.
Article info
Publication history
Published online: May 29, 2022
Accepted:
May 24,
2022
Received in revised form:
April 21,
2022
Received:
January 27,
2022
Declaration: The authors report no financial or commercial conflicts of interest.Identification
Copyright
© 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
