Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis
Background Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potenti...
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| Veröffentlicht in: | Inflammation and Regeneration 2023-10, Vol.43 (1), p.47-47, Article 47 |
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| creator | Zheng, Wenjie Bian, Saiyan Qiu, Shi Bishop, Colin E. Wan, Meimei Xu, Nuo Sun, Xieyin Sequeira, Russel Clive Atala, Anthony Gu, Zhifeng Zhao, Weixin |
| description | Background Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. Methods The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-[beta]1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. Results TGF-[beta]1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-[beta]1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). Conclusion Pd-MSCs-EVs ameliorated TGF-[beta]1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis. Keywords: Mesenchymal stem/stromal cells, Extracellular vesicles, Multicellular organoids, Liver fibrosis, miR-378c |
| doi_str_mv | 10.1186/s41232-023-00297-z |
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| fullrecord | <record><control><sourceid>gale_doaj_</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10557276</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A767906299</galeid><doaj_id>oai_doaj_org_article_2d35a46d0fd84fe7b2cea6cf73495fac</doaj_id><sourcerecordid>A767906299</sourcerecordid><originalsourceid>FETCH-LOGICAL-c513t-c99083fdf8958a6ab3111b491f0ad25098512bb63bc666996710fcc91859b9cb3</originalsourceid><addsrcrecordid>eNpVkktP3DAQx6OqVUGUL9CTj70E_IhfpwqhliKQivo4W2PH3jVykq2dXbF8lH5aHBZVxT54NJ75eTzzb5qPBJ8RosR56QhltMWUtRhTLdvHN80xUQq3imj89j_7qDkt5R7XxQXnRL9vjpiUWklBjpu_dwmcH2dAgy9-dOv9AAmV2Q_I-ZTa3ue48z3yD3OGxbNNkNHOl-iSLwhS8rsIs0ephmUUos1TiQXZPYojuDnuYI7jCq39phpuIae0xC-sguZ1nrarNarPxx8tk8qd_7y5owgeYvnQvAuQij99OU-a31-__Lr81t5-v7q-vLhtHSdsbp3WWLHQB6W5AgGWEUJsp0nA0FOOteKEWiuYdUIIrYUkODinieLaamfZSXN94PYT3JtNjgPkvZkgmmfHlFcG8rz819CecehEj0OvuuClpc6DcEGyTvMArrI-H1ibrR18v3Q2Q3oFfX0zxrVZTTtDMOeSSlEJn14Iefqz9WU2QyxLs2D007YYqmRHudJK19CzQ-gKam1xDNMyo7p7P0Q3jT7E6r-QQmosqF4S6CHB1SGV7MO_wgg2i6rMQVWmqso8q8o8siekTcIV</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2874258989</pqid></control><display><type>article</type><title>Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis</title><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central Open Access</source><source>Springer Nature OA Free Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>SpringerLink Journals - AutoHoldings</source><creator>Zheng, Wenjie ; Bian, Saiyan ; Qiu, Shi ; Bishop, Colin E. ; Wan, Meimei ; Xu, Nuo ; Sun, Xieyin ; Sequeira, Russel Clive ; Atala, Anthony ; Gu, Zhifeng ; Zhao, Weixin</creator><creatorcontrib>Zheng, Wenjie ; Bian, Saiyan ; Qiu, Shi ; Bishop, Colin E. ; Wan, Meimei ; Xu, Nuo ; Sun, Xieyin ; Sequeira, Russel Clive ; Atala, Anthony ; Gu, Zhifeng ; Zhao, Weixin</creatorcontrib><description>Background Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. Methods The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-[beta]1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. Results TGF-[beta]1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-[beta]1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). Conclusion Pd-MSCs-EVs ameliorated TGF-[beta]1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis. Keywords: Mesenchymal stem/stromal cells, Extracellular vesicles, Multicellular organoids, Liver fibrosis, miR-378c</description><identifier>ISSN: 1880-8190</identifier><identifier>ISSN: 1880-9693</identifier><identifier>EISSN: 1880-8190</identifier><identifier>DOI: 10.1186/s41232-023-00297-z</identifier><identifier>PMID: 37798761</identifier><language>eng</language><publisher>London: Springer</publisher><subject>Extracellular vesicles ; Fibrosis ; Health aspects ; Ligases ; Liver diseases ; Liver fibrosis ; Mesenchymal stem/stromal cells ; miR-378c ; Multicellular organoids ; Palladium ; Physiological aspects ; Scientific equipment and supplies industry ; Stem cells ; Transforming growth factors</subject><ispartof>Inflammation and Regeneration, 2023-10, Vol.43 (1), p.47-47, Article 47</ispartof><rights>COPYRIGHT 2023 Springer</rights><rights>Japanese Society of Inflammation and Regeneration 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-c99083fdf8958a6ab3111b491f0ad25098512bb63bc666996710fcc91859b9cb3</citedby><cites>FETCH-LOGICAL-c513t-c99083fdf8958a6ab3111b491f0ad25098512bb63bc666996710fcc91859b9cb3</cites><orcidid>0000-0001-5987-5272</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557276/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557276/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,53790,53792</link.rule.ids></links><search><creatorcontrib>Zheng, Wenjie</creatorcontrib><creatorcontrib>Bian, Saiyan</creatorcontrib><creatorcontrib>Qiu, Shi</creatorcontrib><creatorcontrib>Bishop, Colin E.</creatorcontrib><creatorcontrib>Wan, Meimei</creatorcontrib><creatorcontrib>Xu, Nuo</creatorcontrib><creatorcontrib>Sun, Xieyin</creatorcontrib><creatorcontrib>Sequeira, Russel Clive</creatorcontrib><creatorcontrib>Atala, Anthony</creatorcontrib><creatorcontrib>Gu, Zhifeng</creatorcontrib><creatorcontrib>Zhao, Weixin</creatorcontrib><title>Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis</title><title>Inflammation and Regeneration</title><description>Background Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. Methods The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-[beta]1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. Results TGF-[beta]1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-[beta]1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). Conclusion Pd-MSCs-EVs ameliorated TGF-[beta]1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis. Keywords: Mesenchymal stem/stromal cells, Extracellular vesicles, Multicellular organoids, Liver fibrosis, miR-378c</description><subject>Extracellular vesicles</subject><subject>Fibrosis</subject><subject>Health aspects</subject><subject>Ligases</subject><subject>Liver diseases</subject><subject>Liver fibrosis</subject><subject>Mesenchymal stem/stromal cells</subject><subject>miR-378c</subject><subject>Multicellular organoids</subject><subject>Palladium</subject><subject>Physiological aspects</subject><subject>Scientific equipment and supplies industry</subject><subject>Stem cells</subject><subject>Transforming growth factors</subject><issn>1880-8190</issn><issn>1880-9693</issn><issn>1880-8190</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpVkktP3DAQx6OqVUGUL9CTj70E_IhfpwqhliKQivo4W2PH3jVykq2dXbF8lH5aHBZVxT54NJ75eTzzb5qPBJ8RosR56QhltMWUtRhTLdvHN80xUQq3imj89j_7qDkt5R7XxQXnRL9vjpiUWklBjpu_dwmcH2dAgy9-dOv9AAmV2Q_I-ZTa3ue48z3yD3OGxbNNkNHOl-iSLwhS8rsIs0ephmUUos1TiQXZPYojuDnuYI7jCq39phpuIae0xC-sguZ1nrarNarPxx8tk8qd_7y5owgeYvnQvAuQij99OU-a31-__Lr81t5-v7q-vLhtHSdsbp3WWLHQB6W5AgGWEUJsp0nA0FOOteKEWiuYdUIIrYUkODinieLaamfZSXN94PYT3JtNjgPkvZkgmmfHlFcG8rz819CecehEj0OvuuClpc6DcEGyTvMArrI-H1ibrR18v3Q2Q3oFfX0zxrVZTTtDMOeSSlEJn14Iefqz9WU2QyxLs2D007YYqmRHudJK19CzQ-gKam1xDNMyo7p7P0Q3jT7E6r-QQmosqF4S6CHB1SGV7MO_wgg2i6rMQVWmqso8q8o8siekTcIV</recordid><startdate>20231005</startdate><enddate>20231005</enddate><creator>Zheng, Wenjie</creator><creator>Bian, Saiyan</creator><creator>Qiu, Shi</creator><creator>Bishop, Colin E.</creator><creator>Wan, Meimei</creator><creator>Xu, Nuo</creator><creator>Sun, Xieyin</creator><creator>Sequeira, Russel Clive</creator><creator>Atala, Anthony</creator><creator>Gu, Zhifeng</creator><creator>Zhao, Weixin</creator><general>Springer</general><general>BioMed Central</general><general>BMC</general><scope>AAYXX</scope><scope>CITATION</scope><scope>IAO</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-5987-5272</orcidid></search><sort><creationdate>20231005</creationdate><title>Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis</title><author>Zheng, Wenjie ; Bian, Saiyan ; Qiu, Shi ; Bishop, Colin E. ; Wan, Meimei ; Xu, Nuo ; Sun, Xieyin ; Sequeira, Russel Clive ; Atala, Anthony ; Gu, Zhifeng ; Zhao, Weixin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-c99083fdf8958a6ab3111b491f0ad25098512bb63bc666996710fcc91859b9cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Extracellular vesicles</topic><topic>Fibrosis</topic><topic>Health aspects</topic><topic>Ligases</topic><topic>Liver diseases</topic><topic>Liver fibrosis</topic><topic>Mesenchymal stem/stromal cells</topic><topic>miR-378c</topic><topic>Multicellular organoids</topic><topic>Palladium</topic><topic>Physiological aspects</topic><topic>Scientific equipment and supplies industry</topic><topic>Stem cells</topic><topic>Transforming growth factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Wenjie</creatorcontrib><creatorcontrib>Bian, Saiyan</creatorcontrib><creatorcontrib>Qiu, Shi</creatorcontrib><creatorcontrib>Bishop, Colin E.</creatorcontrib><creatorcontrib>Wan, Meimei</creatorcontrib><creatorcontrib>Xu, Nuo</creatorcontrib><creatorcontrib>Sun, Xieyin</creatorcontrib><creatorcontrib>Sequeira, Russel Clive</creatorcontrib><creatorcontrib>Atala, Anthony</creatorcontrib><creatorcontrib>Gu, Zhifeng</creatorcontrib><creatorcontrib>Zhao, Weixin</creatorcontrib><collection>CrossRef</collection><collection>Gale Academic OneFile</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Inflammation and Regeneration</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Wenjie</au><au>Bian, Saiyan</au><au>Qiu, Shi</au><au>Bishop, Colin E.</au><au>Wan, Meimei</au><au>Xu, Nuo</au><au>Sun, Xieyin</au><au>Sequeira, Russel Clive</au><au>Atala, Anthony</au><au>Gu, Zhifeng</au><au>Zhao, Weixin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis</atitle><jtitle>Inflammation and Regeneration</jtitle><date>2023-10-05</date><risdate>2023</risdate><volume>43</volume><issue>1</issue><spage>47</spage><epage>47</epage><pages>47-47</pages><artnum>47</artnum><issn>1880-8190</issn><issn>1880-9693</issn><eissn>1880-8190</eissn><abstract>Background Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. Methods The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-[beta]1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. Results TGF-[beta]1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-[beta]1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). Conclusion Pd-MSCs-EVs ameliorated TGF-[beta]1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis. Keywords: Mesenchymal stem/stromal cells, Extracellular vesicles, Multicellular organoids, Liver fibrosis, miR-378c</abstract><cop>London</cop><pub>Springer</pub><pmid>37798761</pmid><doi>10.1186/s41232-023-00297-z</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-5987-5272</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Extracellular vesicles Fibrosis Health aspects Ligases Liver diseases Liver fibrosis Mesenchymal stem/stromal cells miR-378c Multicellular organoids Palladium Physiological aspects Scientific equipment and supplies industry Stem cells Transforming growth factors |
| title | Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis |
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