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

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          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.

          Graphical Abstract

          In this study, we identified 3 upregulated fibrotic progression markers (Vimentin, COL5A2, and COL1A1) in the endometrium of IUA patients and highlighted the efficacious therapy of EXOs–HP via inhibiting the fibrosis process.

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          The biology, function, and biomedical applications of exosomes

          The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
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            Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications

            Abstract Exosomes are nano-sized small extracellular vesicles secreted by cells, carrying nucleic acids, proteins, lipids and other bioactive substances to play a role in the body’s physiological and pathological processes. Compared to synthetic carriers such as liposomes and nanoparticles, the endogeneity and heterogeneity of exosomes give them extensive and unique advantages in the field of disease diagnosis and treatment. However, the storage stability, low yield, low purity, and weak targeting of exosomes limit its clinical application. For this reason, further exploration is needed to optimize the above problems and facilitate future functional studies of exosomes. In this paper, the origin, classification, preparation and characterization, storage stability and applications of exosome delivery system are summarized and discussed by searching a large number of literatures.
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              Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics

              Exosomes are small extracellular vesicles with diameters of 30-150 nm. In both physiological and pathological conditions, nearly all types of cells can release exosomes, which play important roles in cell communication and epigenetic regulation by transporting crucial protein and genetic materials such as miRNA, mRNA, and DNA. Consequently, exosome-based disease diagnosis and therapeutic methods have been intensively investigated. However, as in any natural science field, the in-depth investigation of exosomes relies heavily on technological advances. Historically, the two main technical hindrances that have restricted the basic and applied researches of exosomes include, first, how to simplify the extraction and improve the yield of exosomes and, second, how to effectively distinguish exosomes from other extracellular vesicles, especially functional microvesicles. Over the past few decades, although a standardized exosome isolation method has still not become available, a number of techniques have been established through exploration of the biochemical and physicochemical features of exosomes. In this work, by comprehensively analyzing the progresses in exosome separation strategies, we provide a panoramic view of current exosome isolation techniques, providing perspectives toward the development of novel approaches for high-efficient exosome isolation from various types of biological matrices. In addition, from the perspective of exosome-based diagnosis and therapeutics, we emphasize the issue of quantitative exosome and microvesicle separation.
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                Author and article information

                Contributors
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                stcltm
                Stem Cells Translational Medicine
                Oxford University Press (US )
                2157-6564
                2157-6580
                March 2023
                09 March 2023
                09 March 2023
                : 12
                : 3
                : 154-168
                Affiliations
                Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, People’s Republic of China
                Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, People’s Republic of China
                Dr Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University , Hangzhou, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, People’s Republic of China
                Dr Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University , Hangzhou, People’s Republic of China
                Jinhua Institute of Zhejiang University , Jinhua, People’s Republic of China
                Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                Author notes

                Contributed equally as co-first authors.

                Corresponding author: Dan Zhang, PhD, Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310006, People’s Republic of China. Email: zhangdan@ 123456zju.edu.cn ;
                Jianqing Gao, PhD, Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province 310058, People’s Republic of China. Email: gaojianqing@ 123456zju.edu.cn ;
                Runju Zhang, PhD, Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310006, People’s Republic of China. Email: 5311005@ 123456zju.edu.cn
                Author information
                https://orcid.org/0000-0003-1052-7060
                https://orcid.org/0000-0003-1295-4795
                Article
                szad007
                10.1093/stcltm/szad007
                10021501
                36893290
                febc05be-cbc9-4cfb-aef2-74d3a991be75
                © The Author(s) 2023. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

                History
                : 21 August 2022
                : 17 January 2023
                Page count
                Pages: 15
                Funding
                Funded by: National Key Research and Development Program of China, DOI 10.13039/501100012166;
                Award ID: 2022YFC2703500
                Award ID: 2018YFC1005003
                Funded by: National Natural Science Foundation of China, DOI 10.13039/501100001809;
                Award ID: 81974224
                Award ID: 81973252
                Funded by: Key Research and Development Program of Zhejiang Province;
                Award ID: 2021C03098
                Funded by: Zhejiang Province Science and Technology Plan Projects;
                Award ID: LGF22H010006
                Funded by: Zhejiang Provincial Key Medical Technology Program;
                Award ID: WKJ-ZJ-1826
                Categories
                Enabling Technologies for Cell-Based Clinical Translation
                AcademicSubjects/MED00770
                AcademicSubjects/SCI00960

                intrauterine adhesions,endometrial fibrosis,fibrosis biomarkers,exosomes,poloxamer hydrogel

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