Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia
Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluat...
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| Veröffentlicht in: | American journal of physiology. Lung cellular and molecular physiology 2021-05, Vol.320 (5), p.L688-L704 |
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| creator | Porzionato, Andrea Zaramella, Patrizia Dedja, Arben Guidolin, Diego Bonadies, Luca Macchi, Veronica Pozzobon, Michela Jurga, Marcin Perilongo, Giorgio De Caro, Raffaele Baraldi, Eugenio Muraca, Maurizio |
| description | Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks (
= 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (
= 10), or (c) MSC-EVs (
= 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for |
| doi_str_mv | 10.1152/ajplung.00148.2020 |
| format | Article |
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= 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (
= 10), or (c) MSC-EVs (
= 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.</description><identifier>ISSN: 1040-0605</identifier><identifier>EISSN: 1522-1504</identifier><identifier>DOI: 10.1152/ajplung.00148.2020</identifier><identifier>PMID: 33502939</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Administration, Inhalation ; Alveolar air ; Alveoli ; Animals ; Animals, Newborn ; Bronchopulmonary Dysplasia - complications ; CD163 antigen ; CD86 antigen ; Disease Models, Animal ; Dysplasia ; Exposure ; Extracellular vesicles ; Extracellular Vesicles - physiology ; Female ; Fibrosis ; Hyperoxia ; Hyperoxia - physiopathology ; Inflammation ; Injury prevention ; Lung diseases ; Lung Injury - etiology ; Lung Injury - pathology ; Lung Injury - therapy ; Macrophages ; Male ; Mesenchymal Stem Cell Transplantation - methods ; Mesenchymal stem cells ; Mesenchymal Stem Cells - cytology ; Pulmonary Alveoli - cytology ; Pulmonary Alveoli - metabolism ; Pulmonary arteries ; Pulmonary artery ; Pulmonary Artery - cytology ; Pulmonary Artery - metabolism ; Rats ; Rats, Sprague-Dawley ; Saline solutions ; Stem cell transplantation ; Stem cells ; Trachea ; Vesicles</subject><ispartof>American journal of physiology. Lung cellular and molecular physiology, 2021-05, Vol.320 (5), p.L688-L704</ispartof><rights>Copyright American Physiological Society May 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c331t-bd7e6d705b0e66ab176473e4c8cec4be40aca1c8e284051fb04bc7f775c3a4b03</citedby><cites>FETCH-LOGICAL-c331t-bd7e6d705b0e66ab176473e4c8cec4be40aca1c8e284051fb04bc7f775c3a4b03</cites><orcidid>0000-0002-7471-8379 ; 0000-0001-7700-3056</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33502939$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Porzionato, Andrea</creatorcontrib><creatorcontrib>Zaramella, Patrizia</creatorcontrib><creatorcontrib>Dedja, Arben</creatorcontrib><creatorcontrib>Guidolin, Diego</creatorcontrib><creatorcontrib>Bonadies, Luca</creatorcontrib><creatorcontrib>Macchi, Veronica</creatorcontrib><creatorcontrib>Pozzobon, Michela</creatorcontrib><creatorcontrib>Jurga, Marcin</creatorcontrib><creatorcontrib>Perilongo, Giorgio</creatorcontrib><creatorcontrib>De Caro, Raffaele</creatorcontrib><creatorcontrib>Baraldi, Eugenio</creatorcontrib><creatorcontrib>Muraca, Maurizio</creatorcontrib><title>Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia</title><title>American journal of physiology. Lung cellular and molecular physiology</title><addtitle>Am J Physiol Lung Cell Mol Physiol</addtitle><description>Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks (
= 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (
= 10), or (c) MSC-EVs (
= 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.</description><subject>Administration, Inhalation</subject><subject>Alveolar air</subject><subject>Alveoli</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Bronchopulmonary Dysplasia - complications</subject><subject>CD163 antigen</subject><subject>CD86 antigen</subject><subject>Disease Models, Animal</subject><subject>Dysplasia</subject><subject>Exposure</subject><subject>Extracellular vesicles</subject><subject>Extracellular Vesicles - physiology</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Hyperoxia</subject><subject>Hyperoxia - physiopathology</subject><subject>Inflammation</subject><subject>Injury prevention</subject><subject>Lung diseases</subject><subject>Lung Injury - etiology</subject><subject>Lung Injury - pathology</subject><subject>Lung Injury - therapy</subject><subject>Macrophages</subject><subject>Male</subject><subject>Mesenchymal Stem Cell Transplantation - methods</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - cytology</subject><subject>Pulmonary Alveoli - cytology</subject><subject>Pulmonary Alveoli - metabolism</subject><subject>Pulmonary arteries</subject><subject>Pulmonary artery</subject><subject>Pulmonary Artery - cytology</subject><subject>Pulmonary Artery - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Saline solutions</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Trachea</subject><subject>Vesicles</subject><issn>1040-0605</issn><issn>1522-1504</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUcmO1DAQjRCIWX-AA7LEhUt6yluSPqLRACONxAXOkZcK7ZaXYHdG9Nfwq-MwzRyQLJWr6r1XVXpN847ChlLJbtR-9kv8uQGgYtgwYPCqOa8N1lIJ4nX9g4AWOpBnzUUpewCQAN3b5oxzCWzLt-fNn_t4yKo-s0PlibLBRVfWkkuRpIkELBjN7hhqtxwwEIPetxaze0RL8PdKrZXFq0wesTjjsZCMdjE1rusRF_dLdjVzkShidjlFZ0idQEKy6NchutbMLs2LDymqfCT2WGavilNXzZtJ-YLXp3jZ_Ph89_32a_vw7cv97aeH1nBOD622PXa2B6kBu05p2nei5yjMYNAIjQKUUdQMyAYBkk4ahDb91PfScCU08Mvm47PunNOvBcthDK6sh6mIaSkjEwPrOrGVvEI__AfdpyXHut3IJK_qvBtERbFnlMmplIzTOGcX6m0jhXG1bzzZN_61b1ztq6T3J-lFB7QvlH9-8Sdtl5yA</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Porzionato, Andrea</creator><creator>Zaramella, Patrizia</creator><creator>Dedja, Arben</creator><creator>Guidolin, Diego</creator><creator>Bonadies, Luca</creator><creator>Macchi, Veronica</creator><creator>Pozzobon, Michela</creator><creator>Jurga, Marcin</creator><creator>Perilongo, Giorgio</creator><creator>De Caro, Raffaele</creator><creator>Baraldi, Eugenio</creator><creator>Muraca, Maurizio</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TS</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7471-8379</orcidid><orcidid>https://orcid.org/0000-0001-7700-3056</orcidid></search><sort><creationdate>20210501</creationdate><title>Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia</title><author>Porzionato, Andrea ; 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Lung cellular and molecular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Porzionato, Andrea</au><au>Zaramella, Patrizia</au><au>Dedja, Arben</au><au>Guidolin, Diego</au><au>Bonadies, Luca</au><au>Macchi, Veronica</au><au>Pozzobon, Michela</au><au>Jurga, Marcin</au><au>Perilongo, Giorgio</au><au>De Caro, Raffaele</au><au>Baraldi, Eugenio</au><au>Muraca, Maurizio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia</atitle><jtitle>American journal of physiology. Lung cellular and molecular physiology</jtitle><addtitle>Am J Physiol Lung Cell Mol Physiol</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>320</volume><issue>5</issue><spage>L688</spage><epage>L704</epage><pages>L688-L704</pages><issn>1040-0605</issn><eissn>1522-1504</eissn><abstract>Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks (
= 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (
= 10), or (c) MSC-EVs (
= 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>33502939</pmid><doi>10.1152/ajplung.00148.2020</doi><orcidid>https://orcid.org/0000-0002-7471-8379</orcidid><orcidid>https://orcid.org/0000-0001-7700-3056</orcidid></addata></record> |
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| ispartof | American journal of physiology. Lung cellular and molecular physiology, 2021-05, Vol.320 (5), p.L688-L704 |
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| source | MEDLINE; American Physiological Society; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Administration, Inhalation Alveolar air Alveoli Animals Animals, Newborn Bronchopulmonary Dysplasia - complications CD163 antigen CD86 antigen Disease Models, Animal Dysplasia Exposure Extracellular vesicles Extracellular Vesicles - physiology Female Fibrosis Hyperoxia Hyperoxia - physiopathology Inflammation Injury prevention Lung diseases Lung Injury - etiology Lung Injury - pathology Lung Injury - therapy Macrophages Male Mesenchymal Stem Cell Transplantation - methods Mesenchymal stem cells Mesenchymal Stem Cells - cytology Pulmonary Alveoli - cytology Pulmonary Alveoli - metabolism Pulmonary arteries Pulmonary artery Pulmonary Artery - cytology Pulmonary Artery - metabolism Rats Rats, Sprague-Dawley Saline solutions Stem cell transplantation Stem cells Trachea Vesicles |
| title | Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia |
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