Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model

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Abstract

Background

Mesenchymal stem cells (MSCs) have diverse functions in regulating injury and inflammation through the secretion of extracellular vesicles (EVs).

Methods

In this study, we investigated the systemic administration of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (UCMSCs-EVs) as a therapeutic agent for intrauterine adhesions (IUAs) caused by endometrial injury. Additionally, we investigated the therapeutic impact of both UCMSCs-EVs and estrogen either separately or in combination in a rat model. The inflammation, vascularization, proliferation, and extent of fibrosis were assessed by a histopathological and immunohistochemical assessment using transforming growth factor (TGF)-β as a fibrotic marker and vascular endothelial growth factor (VEGF) as a vascular marker. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 (inflammatory cytokines), CD140b (a marker of endometrial stem cells), and RUNX2 (an antifibrotic factor). Finally, Western blotting was used to evaluate collagen I and β-actin expression.

Results

The therapeutic groups treated with either UCMSCs-EVs alone or combined with estrogen exhibited a significant decrease in inflammation and fibrosis (TNF-α, TGF-β, IL-1, IL-6, RUNX2, and collagen-I) as well as a significant decrease in vascularization (VEGF) compared with the untreated rats with IUAs. The most significant results were obtained in animals with IUAs that received a combined therapy of UCMSCs-EVs and estrogen.

Conclusions

We conclude that the synergistic action of human UCMSCs-EVs combined with estrogen provides a highly effective alternative regenerative agent in IUA treatment.

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Most cited references 43

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Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

Xiaoting Liang, Yue Ding, Yuelin Zhang … (2014)

Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.

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Microvesicles Derived from Mesenchymal Stem Cells Enhance Survival in a Lethal Model of Acute Kidney Injury

Stefania Bruno, Cristina Grange, Federica Collino … (2012)

Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.

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Asherman syndrome--one century later.

Dan Yu, Yat-May Wong, Ying Cheong … (2008)

To provide an update on the current knowledge of Asherman syndrome. Literature review. The worldwide reports of this disease. Patients with Asherman syndrome who presented with amenorrhea or hypomenorrhea, infertility, or recurrent pregnancy loss. Hysteroscopy and hysteroscopic surgery have been the gold standard of diagnosis and treatment respectively for this condition. The etiology, pathology, symptomatology, diagnosis, treatment, and reproductive outcomes were analyzed. This syndrome occurs mainly as a result of trauma to the gravid uterine cavity, which leads to the formation of intrauterine and/or intracervical adhesions. Despite the advances in hysteroscopic surgery, the treatment of moderate to severe Asherman syndrome still presents a challenge. Furthermore, pregnancy after treatment remains high risk with complications including spontaneous abortion, preterm delivery, intrauterine growth restriction, placenta accrete or praevia, or even uterine rupture. The management of moderate to severe disease still poses a challenge, and the prognosis of severe disease remains poor. Close antenatal surveillance and monitoring are necessary for women who conceive after treatment.

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Author and article information

Contributors

Nesrine Ebrahim: nesrien.salem@fmed.bu.edu.eg

Ola Mostafa: ola.ali@fmed.bu.edu.eg

Rania Ebrahim El Dosoky: rania.mohamady@fmed.bu.edu.eg

Inas A. Ahmed: inas.ahmed@fmed.bu.edu.eg

Ahmed S. Saad: ahmed.saad@fmed.bu.edu.eg

Abeer Mostafa: abeer.mostafa@kasralainy.edu.eg

Dina Sabry: dinasabry@kasralainy.edu.eg

Khalid Abdelaziz Ibrahim: dr.khalidkhader77@fmed.bu.edu.eg

Ayman Samir Farid:

ORCID: http://orcid.org/0000-0002-7844-7967

ayman.samir@fvtm.bu.edu.eg

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 28 June 2018

Publication date PMC-release: 28 June 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 175

Affiliations

[1 ]ISNI 0000 0004 0621 2741, GRID grid.411660.4, Department of Histology and Cell Biology, Faculty of Medicine, , Benha University, ; Banha, 13518 Qalyubia Egypt

[2 ]ISNI 0000 0004 0621 2741, GRID grid.411660.4, Stem Cell Unit, Faculty of Medicine, , Benha University, ; Banha, 13518 Qalyubia Egypt

[3 ]ISNI 0000 0004 0621 2741, GRID grid.411660.4, Department of Medical Biochemistry, Faculty of Medicine, , Benha University, ; Banha, 13518 Qalyubia Egypt

[4 ]ISNI 0000 0004 0621 2741, GRID grid.411660.4, Molecular Biology and Biotechnology Unit, Faculty of Medicine, , Benha University, ; Banha, 13518 Qalyubia Egypt

[5 ]ISNI 0000 0004 0621 2741, GRID grid.411660.4, Department of Obstetrics and Gynecology, Faculty of Medicine, , Benha University, ; Banha, 13518 Qalyubia Egypt

[6 ]ISNI 0000 0004 0639 9286, GRID grid.7776.1, Department of Medical Biochemistry, Faculty of Medicine, , Cairo University, ; Cairo, 11562 Egypt

[7 ]ISNI 0000 0004 0639 9286, GRID grid.7776.1, Molecular Biology and Stem Cell Unit, Faculty of Medicine, , Cairo University, ; Cairo, 11562 Egypt

[8 ]ISNI 0000 0004 0621 2741, GRID grid.411660.4, Department of Clinical Pathology, Faculty of Veterinary Medicine, , Benha University, ; Moshtohor, Toukh, 13736 Qalyubia Egypt

Author information

Ayman Samir Farid http://orcid.org/0000-0002-7844-7967

Article

Publisher ID: 924

DOI: 10.1186/s13287-018-0924-z

PMC ID: 6027762

PubMed ID: 29954457

SO-VID: c9fd8a89-d6d3-455e-8414-288da000f1cc

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 April 2018

Date revision received : 7 June 2018

Date accepted : 11 June 2018

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: intrauterine adhesions,ucmscs-evs,estrogen,tnf-α,tgf-β,il-1,il-6,runx2,collagen

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: intrauterine adhesions, ucmscs-evs, estrogen, tnf-α, tgf-β, il-1, il-6, runx2, collagen

Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model

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Abstract

Background

Methods

Results

Conclusions

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Bacterial extracellular vesicles

Most cited references 43

Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

Microvesicles Derived from Mesenchymal Stem Cells Enhance Survival in a Lethal Model of Acute Kidney Injury

Asherman syndrome--one century later.

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