Dataset Information

Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

ABSTRACT: Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients.

SUBMITTER: Lin Y

PROVIDER: S-EPMC10021501 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

Lin Yifeng Y Li Yaoshen Y Chen Panpan P Zhang Yanye Y Sun Jiwei J Sun Xiao X Li Jiaqun J Jin Jiani J Xue Jinglei J Zheng Junyan J Jiang Xin-Chi XC Chen Chuan C Li Xiaoqing X Wu Yiqing Y Zhao Wei W Liu Juan J Ye Xiaohang X Zhang Runju R Gao Jianqing J Zhang Dan D

Stem cells translational medicine 20230301 3

Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duratio ...[more]

PMID: 36893290

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Project description:Intrauterine adhesions (IUA), characterized by endometrial fibrosis, is a common cause of uterine infertility. We previously demonstrated that partial epithelial-mesenchymal transition (EMT) and the loss of epithelial homeostasis play a vital role in the development of endometrial fibrosis. As a pro-survival strategy in maintaining cell and tissue homeostasis, macroautophagy/autophagy, conversely, may participate in this process. However, the role of autophagy in endometrial fibrosis remains unknown. Here, we demonstrated that autophagy is defective in endometria of IUA patients, which aggravates EMT and endometrial fibrosis, and defective autophagy is related to DIO2 (iodothyronine deiodinase 2) downregulation. In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process. Mechanistically, silencing DIO2 in EECs blocked autophagic flux and promoted EMT via the MAPK/ERK-MTOR pathway. Inversely, overexpression of DIO2 or triiodothyronine (T3) treatment could restore autophagy and partly reverse EEC-EMT. Furthermore, in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis. Together, we demonstrated that defective autophagy played an important role in EEC-EMT in IUA via the DIO2-MAPK/ERK-MTOR pathway, which provided a potential target for therapeutic implications.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle; AMPK: adenosine 5'-monophosphate-activated protein kinase; AKT/protein kinase B: AKT serine/threonine kinase; ATG: autophagy related; CDH1/E-cadherin: cadherin 1; CDH2/N-cadherin: cadherin 2; CQ: chloroquine; CTSD: cathepsin D; DIO2: iodothyronine deiodinase 2; DEGs: differentially expressed genes; EECs: endometrial epithelial cells; EMT: epithelial-mesenchymal transition; FN1: fibronectin 1; IUA: intrauterine adhesions; LAMP1: lysosomal associated membrane protein 1; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; T3: triiodothyronine; T4: tetraiodothyronine; TFEB: transcription factor EB; PBS: phosphate-buffered saline; TEM: transmission electron microscopy; TGFB/TGFβ: transforming growth factor beta.

Project description:BackgroundIntrauterine adhesions (IUA) is one of the most common gynecological diseases and main causes of uterine infertility. Among proposed hypotheses on IUA development, the reduced endometrial regeneration resulting from loss of functional stem cells has been proposed as the key factor affecting the IUA prognosis. However, the underlying mechanisms mostly remain unclear. Because the eMSCs (endometrial mesenchymal stem/stromal cells) play a critical role in both supporting the gland development and also preparing the environment for embryo implantation through decidualization, the characteristics and functions were compared between the eMSCs derived from IUA and non-IUA patients, to uncover the important roles of eMSCs in IUA and also the underlying mechanisms.MethodsEndometrium biopsies were collected from IUA patients and controls. The fibrosis features and eMSC distributions were investigated with IHC (immunohistochemistry). Then the eMSCs were isolated and their functions and characteristics were analyzed in vitro.ResultsOur results indicate that the scar tissues in IUA are characterized with hyper-activation of pro-fibrotic fibroblast and myo-differentiation, along with reduced number of eMSCs. The isolated eMSCs from IUA and controls show similar functions from the perspectives of cell morphology, proliferation, colony formation, exosome secretion, positive ratio of eMSC markers and conventional MSC markers, tri-differentiation efficiency, the ability of suppressing lymphocyte proliferation, cell aging, and promoting vascular tube formation. However, the eMSCs from IUA have reduced levels of decidualization and higher levels of cell migration, invasion, and also myofibroblast differentiation. Further investigations indicate that the TGF-β pathway, which is the major inducer of myofibroblast differentiation, is up-regulated and responsible for the enhanced myofibroblast differentiation potential of eMSCs from IUA.ConclusionsIn conclusion, we have demonstrated here that the scar tissues in IUA biopsy are characterized with enhanced differentiation of pro-fibrotic fibroblast and myofibroblast. The number of eMSCs is reduced in IUA tissues, and their myofibroblast differentiation capability is increased.

Dataset Information

Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

Publications

Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

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