Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase

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Abstract

Background

Repair deficiency after endometrial injury is an important reason for intra-uterine adhesions, amenorrhea, and infertility in females. Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is effective in repairing the damaged endometrium. However, the possibility of using umbilical cord-derived MSCs (UC-MSCs) to treat endometrial injury is rarely reported.

Methods

Ethanol (95%) was injected into rat uterus to establish a model of endometrial injury. UC-MSCs were injected through the tail vein, either as a single, twice, or thrice administration. Functional restoration of the uterus was assessed by testing embryo implantation rates. Endometrial morphological alteration was observed by hematoxylin and eosin staining. Endometrial fibrosis, markers of epithelial and stromal cells of endometrium, cell proliferation and angiogenesis, and inflammatory factors were detected using immunohistochemistry, Western blotting, and quantitative reverse-transcription polymerase chain reaction.

Results

Endometrial morphology and embryo implantation rates were significantly improved on day 8 of transplantation among single-, twice-, or thrice-administered rats. Moreover, UC-MSCs could alleviate fibrosis in general, and reduced the expression of fibrosis markers, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β. The cell proliferation marker Ki-67 had a positive expression in the injured endometrium after UC-MSC transplantation. The endometrial stromal marker vimentin and epithelial marker cytokeratin-19 (CK-19) expressions were visibly increased. The expression of vascular markers CD31, vascular endothelial growth factor (VEGF)A, and matrix metalloprotein (MMP)9 was generally upregulated. Proinflammatory factors interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2 were significantly downregulated in the rats administered UC-MSCs twice and thrice.

Conclusions

UC-MSC transplantation contributed to the repair of endometrial injury and restoration of fertility, likely through the suppression of excessive fibrosis and inflammation, and enhancement of endometrial cell proliferation and vascular remodeling.

Electronic supplementary material

The online version of this article (10.1186/s13287-018-0777-5) contains supplementary material, which is available to authorized users.

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Most cited references 28

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Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue

June Seok Heo, YOUJEONG CHOI, Han-Soo Kim … (2015)

Mesenchymal stem cells (MSCs) are clinically useful due to their capacity for self-renewal, their immunomodulatory properties and tissue regenerative potential. These cells can be isolated from various tissues and exhibit different potential for clinical applications according to their origin, and thus comparative studies on MSCs from different tissues are essential. In this study, we investigated the immunophenotype, proliferative potential, multilineage differentiation and immunomodulatory capacity of MSCs derived from different tissue sources, namely bone marrow, adipose tissue, the placenta and umbilical cord blood. The gene expression profiles of stemness-related genes [octamer-binding transcription factor 4 (OCT4), sex determining region Y-box (SOX)2, MYC, Krüppel-like factor 4 (KLF4), NANOG, LIN28 and REX1] and lineage-related and differentiation stage-related genes [B4GALNT1 (GM2/GS2 synthase), inhibin, beta A (INHBA), distal-less homeobox 5 (DLX5), runt-related transcription factor 2 (RUNX2), proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein alpha (C/EBPA), bone morphogenetic protein 7 (BMP7) and SOX9] were compared using RT-PCR. No significant differences in growth rate, colony-forming efficiency and immunophenotype were observed. Our results demonstrated that MSCs derived from bone marrow and adipose tissue shared not only in vitro trilineage differentiation potential, but also gene expression profiles. While there was considerable interdonor variation in DLX5 expression between MSCs derived from different tissues, its expression appears to be associated with the osteogenic potential of MSCs. Bone marrow-derived MSCs (BM-MSCs) significantly inhibited allogeneic T cell proliferation possibly via the high levels of the immunosuppressive cytokines, IL10 and TGFB1. Although MSCs derived from different tissues and fibroblasts share many characteristics, some of the marker genes, such as B4GALNT1 and DLX5 may be useful for the characterization of MSCs derived from different tissue sources. Collectively, our results suggest that, based on their tri-lineage differentiation potential and immunomodulatory effects, BM-MSCs and adipose tissue-derived MSCs (A-MSCs) represent the optimal stem cell source for tissue engineering and regenerative medicine.

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Review of intrauterine adhesions.

Rebecca Deans, Jason Abbott (2015)

This article has been produced to review the literature on symptomatic and asymptomatic intrauterine adhesions. Electronic resources including Medline, PubMed, CINAHL, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Current Contents, and EMBASE were searched using the Medical Subject Headings (MeSH), including all subheadings, and the keywords "Asherman syndrome," "Hysteroscopic lysis of adhesions," "Hysteroscopic synechiolysis," "Hysteroscopy and adhesion," "Intrauterine adhesions," "Intrauterine septum and synechiae," and "Obstetric outcomes after intrauterine surgery." The vast majority of evidence in the literature consists of uncontrolled case series, with only intrauterine adhesion barriers being assessed in a randomized controlled format. This article reviews epidemiology, pathologic features, classification systems, and treatments. Seven classification systems are described, with no universal acceptance of any one system and no validation of any of them. Hysteroscopy is the mainstay of both diagnosis and treatment, with medical treatments having no role in management. There is a wide range of treatment techniques with no controlled comparative studies, and assessments are descriptive and report fertility and menstrual outcomes, with more severe adhesions having the worst clinical outcomes. One of the most important features of treatment is prevention of recurrence, with the best available evidence demonstrating that newly developed adhesion barriers such as hyaluronic acid show promise for preventing new adhesions. Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.

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Th1-type immunity is incompatible with successful pregnancy.

R Raghupathy (1997)

Several years ago, the rather provocative question was raised: is successful pregnancy a T helper 2 (Th2) phenomenon? Implicit in this argument is the corollary that unsuccessful pregnancy is a Th1-type situation. Here, evidence from murine and human pregnancy is presented to show that, since Th1-type cytokines mediate pregnancy loss, a shift towards Th1-type immunity may help resolve 'unexplained' pregnancy failure.

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Author and article information

Contributors

Xu Ma: +86-010-62178932 , genetic@263.net.cn

Hong-Fei Xia: +86-010-62178932 , hongfeixia@126.com

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): 13 February 2018

Publication date PMC-release: 13 February 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 36

Affiliations

[1 ]Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, 100081 China

[2 ]ISNI 0000 0001 0662 3178, GRID grid.12527.33, Graduate School, Peking Union Medical College, ; Beijing, China

[3 ]Haidian Maternal & Child Health Hospital, Beijing, China

Article

Publisher ID: 777

DOI: 10.1186/s13287-018-0777-5

PMC ID: 5810045

PubMed ID: 29433563

SO-VID: 028b2926-93d2-471a-8b91-96a0d59dea07

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 : 29 September 2017

Date revision received : 4 December 2017

Date accepted : 15 January 2018

Funding

Funded by: Beijing Natural Science Foundation of China

Award ID: No. 7172163

Funded by: The National Key Research and Development Program of China

Award ID: 2016YFC1000803 and 2016YFC1000307-5

Funded by: National Research Institute for Family Planning

Award ID: No. 2015GJZ01

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ScienceOpen disciplines: Molecular medicine

Keywords: uc-mscs transplantation,injured rat endometrium,chronic phase,therapeutic effect and mechanism

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ScienceOpen disciplines: Molecular medicine

Keywords: uc-mscs transplantation, injured rat endometrium, chronic phase, therapeutic effect and mechanism

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Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Bacterial extracellular vesicles

Most cited references 28

Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue

Review of intrauterine adhesions.

Th1-type immunity is incompatible with successful pregnancy.

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Cited by 88

Most referenced authors 469