Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles
microRNAs (miRs), a novel class of small non-coding RNAs, are involved in cell proliferation, differentiation, development, and death. In this study, we found that miR-221 translocation by microvesicles (MVs) plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal st...
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| Veröffentlicht in: | PloS one 2013-08, Vol.8 (8), p.e73304-e73304 |
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| creator | Yu, Bin Gong, Min Wang, Yigang Millard, Ronald W Pasha, Zeeshan Yang, Yueting Ashraf, Muhammad Xu, Meifeng |
| description | microRNAs (miRs), a novel class of small non-coding RNAs, are involved in cell proliferation, differentiation, development, and death. In this study, we found that miR-221 translocation by microvesicles (MVs) plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal stem cells (MSC).
Adult rat bone marrow MSC and neonatal rat ventricle cardiomyocytes (CM) were harvested as primary cultures. MSC were transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus (pMSCV) retroviral expression system. Empty vector transfection was used as a control (MSC(Null)). The expression of miRs was assessed by real-time PCR and localized using in situ hybridization (ISH). MVs collected from MSC cultures were characterized by expression of CD9, CD63, and HSP70, and photographed with electron microscopy. Cardioprotection during hypoxia afforded by conditioned medium (CdM) from MSC cultures was evaluated by lactate dehydrogenase (LDH) release, MTS uptake by CM, and caspase 3/7 activity. Expression of miR-221/222 was significantly higher in MSC than in CM and miR-221 was upregulated in MSC(GATA-4). MSC overexpression of miR-221 significantly enhanced cardioprotection by reducing the expression of p53 upregulated modulator of apoptosis (PUMA). Moreover, expression of PUMA was significantly decreased in CM co-cultured with MSC. MVs derived from MSC expressed high levels of miR-221, and were internalized quickly by CM as documented in images obtained from a Time-Lapse Imaging System.
Our results demonstrate that cardioprotection by MSC(GATA-4) may be regulated in part by a transfer of anti-apoptotic miRs contained within MVs. |
| doi_str_mv | 10.1371/journal.pone.0073304 |
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Adult rat bone marrow MSC and neonatal rat ventricle cardiomyocytes (CM) were harvested as primary cultures. MSC were transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus (pMSCV) retroviral expression system. Empty vector transfection was used as a control (MSC(Null)). The expression of miRs was assessed by real-time PCR and localized using in situ hybridization (ISH). MVs collected from MSC cultures were characterized by expression of CD9, CD63, and HSP70, and photographed with electron microscopy. Cardioprotection during hypoxia afforded by conditioned medium (CdM) from MSC cultures was evaluated by lactate dehydrogenase (LDH) release, MTS uptake by CM, and caspase 3/7 activity. Expression of miR-221/222 was significantly higher in MSC than in CM and miR-221 was upregulated in MSC(GATA-4). MSC overexpression of miR-221 significantly enhanced cardioprotection by reducing the expression of p53 upregulated modulator of apoptosis (PUMA). Moreover, expression of PUMA was significantly decreased in CM co-cultured with MSC. MVs derived from MSC expressed high levels of miR-221, and were internalized quickly by CM as documented in images obtained from a Time-Lapse Imaging System.
Our results demonstrate that cardioprotection by MSC(GATA-4) may be regulated in part by a transfer of anti-apoptotic miRs contained within MVs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0073304</identifier><identifier>PMID: 24015301</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiogenesis ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - metabolism ; Biology ; Bone marrow ; Cardiomyocytes ; Caspase ; Caspase-3 ; CD63 antigen ; CD9 antigen ; Cell Hypoxia - genetics ; Cell proliferation ; Cloning ; Coculture Techniques ; Conditioning ; Electron microscopy ; GATA-4 gene ; GATA4 Transcription Factor - genetics ; GATA4 Transcription Factor - metabolism ; Heart ; Heart Ventricles - cytology ; Heart Ventricles - metabolism ; Hsp70 protein ; Hypoxia ; Ischemia ; L-Lactate dehydrogenase ; Laboratory animals ; Lactate dehydrogenase ; Lactic acid ; Male ; Medicine ; Mesenchymal stem cells ; Mesenchymal Stromal Cells - cytology ; Mesenchymal Stromal Cells - metabolism ; Mesenchyme ; MicroRNAs ; MicroRNAs - biosynthesis ; MicroRNAs - genetics ; miRNA ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - metabolism ; Neonates ; p53 Protein ; Pathology ; Penicillin ; Rats ; Rats, Sprague-Dawley ; Rodents ; Stem cell transplantation ; Stem cells ; Studies ; Transfection ; Translocation ; Transplants & implants ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Ventricle ; Viruses</subject><ispartof>PloS one, 2013-08, Vol.8 (8), p.e73304-e73304</ispartof><rights>2013 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Yu et al 2013 Yu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-8031014cef4a86e2340b11b0533a78453d6b842909bdc44ba0b18aa13324e40d3</citedby><cites>FETCH-LOGICAL-c592t-8031014cef4a86e2340b11b0533a78453d6b842909bdc44ba0b18aa13324e40d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756018/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756018/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24015301$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Qin, Gangjian</contributor><creatorcontrib>Yu, Bin</creatorcontrib><creatorcontrib>Gong, Min</creatorcontrib><creatorcontrib>Wang, Yigang</creatorcontrib><creatorcontrib>Millard, Ronald W</creatorcontrib><creatorcontrib>Pasha, Zeeshan</creatorcontrib><creatorcontrib>Yang, Yueting</creatorcontrib><creatorcontrib>Ashraf, Muhammad</creatorcontrib><creatorcontrib>Xu, Meifeng</creatorcontrib><title>Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>microRNAs (miRs), a novel class of small non-coding RNAs, are involved in cell proliferation, differentiation, development, and death. In this study, we found that miR-221 translocation by microvesicles (MVs) plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal stem cells (MSC).
Adult rat bone marrow MSC and neonatal rat ventricle cardiomyocytes (CM) were harvested as primary cultures. MSC were transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus (pMSCV) retroviral expression system. Empty vector transfection was used as a control (MSC(Null)). The expression of miRs was assessed by real-time PCR and localized using in situ hybridization (ISH). MVs collected from MSC cultures were characterized by expression of CD9, CD63, and HSP70, and photographed with electron microscopy. Cardioprotection during hypoxia afforded by conditioned medium (CdM) from MSC cultures was evaluated by lactate dehydrogenase (LDH) release, MTS uptake by CM, and caspase 3/7 activity. Expression of miR-221/222 was significantly higher in MSC than in CM and miR-221 was upregulated in MSC(GATA-4). MSC overexpression of miR-221 significantly enhanced cardioprotection by reducing the expression of p53 upregulated modulator of apoptosis (PUMA). Moreover, expression of PUMA was significantly decreased in CM co-cultured with MSC. MVs derived from MSC expressed high levels of miR-221, and were internalized quickly by CM as documented in images obtained from a Time-Lapse Imaging System.
Our results demonstrate that cardioprotection by MSC(GATA-4) may be regulated in part by a transfer of anti-apoptotic miRs contained within MVs.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Biology</subject><subject>Bone marrow</subject><subject>Cardiomyocytes</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>CD63 antigen</subject><subject>CD9 antigen</subject><subject>Cell Hypoxia - genetics</subject><subject>Cell proliferation</subject><subject>Cloning</subject><subject>Coculture Techniques</subject><subject>Conditioning</subject><subject>Electron microscopy</subject><subject>GATA-4 gene</subject><subject>GATA4 Transcription Factor - genetics</subject><subject>GATA4 Transcription Factor - metabolism</subject><subject>Heart</subject><subject>Heart Ventricles - cytology</subject><subject>Heart Ventricles - metabolism</subject><subject>Hsp70 protein</subject><subject>Hypoxia</subject><subject>Ischemia</subject><subject>L-Lactate dehydrogenase</subject><subject>Laboratory animals</subject><subject>Lactate dehydrogenase</subject><subject>Lactic acid</subject><subject>Male</subject><subject>Medicine</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stromal Cells - cytology</subject><subject>Mesenchymal Stromal Cells - metabolism</subject><subject>Mesenchyme</subject><subject>MicroRNAs</subject><subject>MicroRNAs - biosynthesis</subject><subject>MicroRNAs - genetics</subject><subject>miRNA</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Neonates</subject><subject>p53 Protein</subject><subject>Pathology</subject><subject>Penicillin</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rodents</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Transfection</subject><subject>Translocation</subject><subject>Transplants & implants</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Ventricle</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUttq3DAQNaWlubR_UFpBX_LirW6-vRSWpU0DgUJJn8VYHm-0yNJW8gb8D_noylknJKV60aA5c3TOYbLsA6MrJir2ZecPwYFd7b3DFaWVEFS-yk5ZI3hecipeP6tPsrMYd5QWoi7Lt9kJl5QVgrLT7H4DoTN-mLyeRiT74EfUo_GOtBO5XN-sc0m26JCg2xqHGLAjA0Z0-nYawJI44kA0WhuJiWQPYTRg7ZQwnYExgRPNGMBF6zU88PqeDOZXzjkjxqVSB3-H0WiL8V32pgcb8f1yn2e_v3-72fzIr39eXm3W17kuGj7mNRWMMqmxl1CXyIWkLWNtciegqmUhurKtJW9o03ZayhZSuwZgQnCJknbiPPt05N1bH9USZFRM8rqQTSXrhLg6IjoPO7UPZoAwKQ9GPTz4sFWz1SRasaLo21Zo3SNK6GmTTiX7quoK0ZYAievr8tuhTbFodCkQ-4L0ZceZW7X1d0pURUnZLOZiIQj-zwHjqAYT58zBoT_MugXjTS1ZmaCf_4H-3508olL2MQbsn8QwqublepxS83KpZbnS2MfnRp6GHrdJ_AUtGs7D</recordid><startdate>20130828</startdate><enddate>20130828</enddate><creator>Yu, Bin</creator><creator>Gong, Min</creator><creator>Wang, Yigang</creator><creator>Millard, Ronald W</creator><creator>Pasha, Zeeshan</creator><creator>Yang, Yueting</creator><creator>Ashraf, Muhammad</creator><creator>Xu, Meifeng</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130828</creationdate><title>Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles</title><author>Yu, Bin ; Gong, Min ; Wang, Yigang ; Millard, Ronald W ; Pasha, Zeeshan ; Yang, Yueting ; Ashraf, Muhammad ; Xu, Meifeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-8031014cef4a86e2340b11b0533a78453d6b842909bdc44ba0b18aa13324e40d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Bin</au><au>Gong, Min</au><au>Wang, Yigang</au><au>Millard, Ronald W</au><au>Pasha, Zeeshan</au><au>Yang, Yueting</au><au>Ashraf, Muhammad</au><au>Xu, Meifeng</au><au>Qin, Gangjian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-08-28</date><risdate>2013</risdate><volume>8</volume><issue>8</issue><spage>e73304</spage><epage>e73304</epage><pages>e73304-e73304</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>microRNAs (miRs), a novel class of small non-coding RNAs, are involved in cell proliferation, differentiation, development, and death. In this study, we found that miR-221 translocation by microvesicles (MVs) plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal stem cells (MSC).
Adult rat bone marrow MSC and neonatal rat ventricle cardiomyocytes (CM) were harvested as primary cultures. MSC were transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus (pMSCV) retroviral expression system. Empty vector transfection was used as a control (MSC(Null)). The expression of miRs was assessed by real-time PCR and localized using in situ hybridization (ISH). MVs collected from MSC cultures were characterized by expression of CD9, CD63, and HSP70, and photographed with electron microscopy. Cardioprotection during hypoxia afforded by conditioned medium (CdM) from MSC cultures was evaluated by lactate dehydrogenase (LDH) release, MTS uptake by CM, and caspase 3/7 activity. Expression of miR-221/222 was significantly higher in MSC than in CM and miR-221 was upregulated in MSC(GATA-4). MSC overexpression of miR-221 significantly enhanced cardioprotection by reducing the expression of p53 upregulated modulator of apoptosis (PUMA). Moreover, expression of PUMA was significantly decreased in CM co-cultured with MSC. MVs derived from MSC expressed high levels of miR-221, and were internalized quickly by CM as documented in images obtained from a Time-Lapse Imaging System.
Our results demonstrate that cardioprotection by MSC(GATA-4) may be regulated in part by a transfer of anti-apoptotic miRs contained within MVs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24015301</pmid><doi>10.1371/journal.pone.0073304</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1428549748 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Angiogenesis Animals Apoptosis Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Biology Bone marrow Cardiomyocytes Caspase Caspase-3 CD63 antigen CD9 antigen Cell Hypoxia - genetics Cell proliferation Cloning Coculture Techniques Conditioning Electron microscopy GATA-4 gene GATA4 Transcription Factor - genetics GATA4 Transcription Factor - metabolism Heart Heart Ventricles - cytology Heart Ventricles - metabolism Hsp70 protein Hypoxia Ischemia L-Lactate dehydrogenase Laboratory animals Lactate dehydrogenase Lactic acid Male Medicine Mesenchymal stem cells Mesenchymal Stromal Cells - cytology Mesenchymal Stromal Cells - metabolism Mesenchyme MicroRNAs MicroRNAs - biosynthesis MicroRNAs - genetics miRNA Myocytes, Cardiac - cytology Myocytes, Cardiac - metabolism Neonates p53 Protein Pathology Penicillin Rats Rats, Sprague-Dawley Rodents Stem cell transplantation Stem cells Studies Transfection Translocation Transplants & implants Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Ventricle Viruses |
| title | Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T16%3A22%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cardiomyocyte%20protection%20by%20GATA-4%20gene%20engineered%20mesenchymal%20stem%20cells%20is%20partially%20mediated%20by%20translocation%20of%20miR-221%20in%20microvesicles&rft.jtitle=PloS%20one&rft.au=Yu,%20Bin&rft.date=2013-08-28&rft.volume=8&rft.issue=8&rft.spage=e73304&rft.epage=e73304&rft.pages=e73304-e73304&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0073304&rft_dat=%3Cproquest_plos_%3E1431298416%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1428549748&rft_id=info:pmid/24015301&rft_doaj_id=oai_doaj_org_article_155fbb3ccfee4af0999974f77d53b6aa&rfr_iscdi=true |