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Endometriotic mesenchymal stem cells significantly promote fibrogenesis in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of TGF-β1 and Wnt1.
Hum Reprod. 2016 06; 31(6):1224-35.HR

Abstract

STUDY QUESTION

Are endometriotic mesenchymal stem cells (Ecto-MSCs) involved in the fibrosis of ovarian endometrioma?

SUMMARY ANSWER

Ecto-MSCs enhanced the fibrotic behavior of stromal cells in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of transforming growth factor-β1 (TGF-β1) and Wnt1.

WHAT IS KNOWN ALREADY

Endometriosis is characterized by ectopic outgrowth of endometrial stroma and glands surrounded by dense fibrous tissues. The pathogenesis of endometriosis, especially ovarian endometrioma-associated fibrosis, is still unknown.

STUDY DESIGN, SIZE, DURATION

We analyzed endometrial samples from 15 patients of reproductive age with ovarian endometrioma and normal menstrual cycles. A total of 54 nude mice received a single injection of proliferative endometrial fragments from 14 individuals without endometriosis.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Conditioned medium (CM) was collected from endometrial mesenchymal stem cells (Euto-MSCs) and Ecto-MSCs. The effects of CM on cell proliferation, migration, invasion and collagen gel contraction of endometrial and endometriotic stromal cells (Euto- and Ecto-ESCs) in ovarian endometrioma were evaluated by cell counting kit-8, transwell and collagen gel contraction assays. Effects of CM on fibrotic markers' expression [including α-smooth muscle actin, Type I collagen, connective tissue growth factor and fibronectin (FN)] in Euto- and Ecto-ESCs were determined by real-time reverse-transcription-polymerase chain reaction and western blotting. Additionally, fibrogenic effects of Ecto-MSC CM treatment on endometriotic implants were analyzed using a xenograft model of endometriosis in immunodeficient nude mice.

MAIN RESULTS AND THE ROLE OF CHANCE

Our results demonstrated that Ecto-MSC CM significantly promoted cell proliferation, migration, invasion and collagen gel contraction of Euto- and Ecto-ESCs from patients with ovarian endometrioma compared with control and Euto-MSC CM. Expression levels of fibrotic markers in Euto- and Ecto-ESCs were dramatically elevated after treatment with Ecto-MSC CM. Ecto-MSCs secreted higher levels of TGF-β1 and Wnt1 compared with Euto-MSCs. Furthermore, both TGF-β1 and Wnt1 significantly increased expression of fibrotic markers in Euto- and Ecto-ESCs, which was reversed by an anti-TGF-β1 antibody or Wnt1 negative regulator, Dickkopf-related protein 1 (Dkk1). Mechanistic studies demonstrated that Wnt/β-catenin signaling pathways in stromal cells were activated by Ecto-MSC CM. Animal experiments showed that TGF-β1 and Wnt1 as well as Ecto-MSC CM markedly increased the expression of FN and collagen I, which enhanced the progression of fibrosis in endometriosis.

LIMITATIONS, REASONS FOR CAUTION

To our knowledge, this is the first study to identify the role of Ecto-MSCs in the pathogenesis of fibrosis in ovarian endometrioma. However, numerous other growth factors and cell types may also be involved in the pathogenesis. Therefore, further studies are required to elucidate the paracrine effects of cells in ovarian endometrioma.

WIDER IMPLICATIONS OF THE FINDINGS

Ecto-MSCs may be involved in the pathogenesis of fibrosis in ovarian endometrioma.

STUDY FUNDING/COMPETING INTERESTS

This study was supported in part by the National Natural Science Foundation of China (81471505 and 81270657). No competing interests are declared.

Authors+Show Affiliations

Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou 310016, China.Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou 310016, China.Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou 310016, China.Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou 310016, China.Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou 310016, China zhangsongying@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27005891

Citation

Li, Jing, et al. "Endometriotic Mesenchymal Stem Cells Significantly Promote Fibrogenesis in Ovarian Endometrioma Through the Wnt/β-catenin Pathway By Paracrine Production of TGF-β1 and Wnt1." Human Reproduction (Oxford, England), vol. 31, no. 6, 2016, pp. 1224-35.
Li J, Dai Y, Zhu H, et al. Endometriotic mesenchymal stem cells significantly promote fibrogenesis in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of TGF-β1 and Wnt1. Hum Reprod. 2016;31(6):1224-35.
Li, J., Dai, Y., Zhu, H., Jiang, Y., & Zhang, S. (2016). Endometriotic mesenchymal stem cells significantly promote fibrogenesis in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of TGF-β1 and Wnt1. Human Reproduction (Oxford, England), 31(6), 1224-35. https://doi.org/10.1093/humrep/dew058
Li J, et al. Endometriotic Mesenchymal Stem Cells Significantly Promote Fibrogenesis in Ovarian Endometrioma Through the Wnt/β-catenin Pathway By Paracrine Production of TGF-β1 and Wnt1. Hum Reprod. 2016;31(6):1224-35. PubMed PMID: 27005891.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endometriotic mesenchymal stem cells significantly promote fibrogenesis in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of TGF-β1 and Wnt1. AU - Li,Jing, AU - Dai,Yongdong, AU - Zhu,Haiyan, AU - Jiang,Yinshen, AU - Zhang,Songying, Y1 - 2016/03/22/ PY - 2015/11/25/received PY - 2016/03/01/accepted PY - 2016/3/24/entrez PY - 2016/3/24/pubmed PY - 2018/3/6/medline KW - TGF-β1 KW - Wnt1 KW - fibrosis KW - mesenchymal stem cells KW - ovarian endometrioma SP - 1224 EP - 35 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 31 IS - 6 N2 - STUDY QUESTION: Are endometriotic mesenchymal stem cells (Ecto-MSCs) involved in the fibrosis of ovarian endometrioma? SUMMARY ANSWER: Ecto-MSCs enhanced the fibrotic behavior of stromal cells in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of transforming growth factor-β1 (TGF-β1) and Wnt1. WHAT IS KNOWN ALREADY: Endometriosis is characterized by ectopic outgrowth of endometrial stroma and glands surrounded by dense fibrous tissues. The pathogenesis of endometriosis, especially ovarian endometrioma-associated fibrosis, is still unknown. STUDY DESIGN, SIZE, DURATION: We analyzed endometrial samples from 15 patients of reproductive age with ovarian endometrioma and normal menstrual cycles. A total of 54 nude mice received a single injection of proliferative endometrial fragments from 14 individuals without endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Conditioned medium (CM) was collected from endometrial mesenchymal stem cells (Euto-MSCs) and Ecto-MSCs. The effects of CM on cell proliferation, migration, invasion and collagen gel contraction of endometrial and endometriotic stromal cells (Euto- and Ecto-ESCs) in ovarian endometrioma were evaluated by cell counting kit-8, transwell and collagen gel contraction assays. Effects of CM on fibrotic markers' expression [including α-smooth muscle actin, Type I collagen, connective tissue growth factor and fibronectin (FN)] in Euto- and Ecto-ESCs were determined by real-time reverse-transcription-polymerase chain reaction and western blotting. Additionally, fibrogenic effects of Ecto-MSC CM treatment on endometriotic implants were analyzed using a xenograft model of endometriosis in immunodeficient nude mice. MAIN RESULTS AND THE ROLE OF CHANCE: Our results demonstrated that Ecto-MSC CM significantly promoted cell proliferation, migration, invasion and collagen gel contraction of Euto- and Ecto-ESCs from patients with ovarian endometrioma compared with control and Euto-MSC CM. Expression levels of fibrotic markers in Euto- and Ecto-ESCs were dramatically elevated after treatment with Ecto-MSC CM. Ecto-MSCs secreted higher levels of TGF-β1 and Wnt1 compared with Euto-MSCs. Furthermore, both TGF-β1 and Wnt1 significantly increased expression of fibrotic markers in Euto- and Ecto-ESCs, which was reversed by an anti-TGF-β1 antibody or Wnt1 negative regulator, Dickkopf-related protein 1 (Dkk1). Mechanistic studies demonstrated that Wnt/β-catenin signaling pathways in stromal cells were activated by Ecto-MSC CM. Animal experiments showed that TGF-β1 and Wnt1 as well as Ecto-MSC CM markedly increased the expression of FN and collagen I, which enhanced the progression of fibrosis in endometriosis. LIMITATIONS, REASONS FOR CAUTION: To our knowledge, this is the first study to identify the role of Ecto-MSCs in the pathogenesis of fibrosis in ovarian endometrioma. However, numerous other growth factors and cell types may also be involved in the pathogenesis. Therefore, further studies are required to elucidate the paracrine effects of cells in ovarian endometrioma. WIDER IMPLICATIONS OF THE FINDINGS: Ecto-MSCs may be involved in the pathogenesis of fibrosis in ovarian endometrioma. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the National Natural Science Foundation of China (81471505 and 81270657). No competing interests are declared. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/27005891/Endometriotic_mesenchymal_stem_cells_significantly_promote_fibrogenesis_in_ovarian_endometrioma_through_the_Wnt/β_catenin_pathway_by_paracrine_production_of_TGF_β1_and_Wnt1_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dew058 DB - PRIME DP - Unbound Medicine ER -