CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury
The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. H...
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| Veröffentlicht in: | Theranostics 2023-01, Vol.13 (6), p.1759-1773 |
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| creator | Qi, Tingting Xu, Xiaoming Guo, Yongzhen Xia, Yunlong Peng, Lu Li, Congye Ding, Fengyue Gao, Chao Fan, Miaomiao Yu, Min Zhao, Huishou He, Yuan Li, Wenli Hai, Chunxu Gao, Erhe Zhang, Xing Gao, Feng Fan, Yanhong Yan, Wenjun Tao, Ling |
| description | The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections. We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure.
Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice.
experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB.
We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependen |
| doi_str_mv | 10.7150/thno.81336 |
| format | Article |
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Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice.
experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB.
We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependent STAT5/RNF4 activation.</description><identifier>ISSN: 1838-7640</identifier><identifier>EISSN: 1838-7640</identifier><identifier>DOI: 10.7150/thno.81336</identifier><identifier>PMID: 37064880</identifier><language>eng</language><publisher>Australia: Ivyspring International Publisher Pty Ltd</publisher><subject>Adenoviruses ; Animals ; Apoptosis ; Body fat ; Cardiac function ; Cardiovascular disease ; Chemokines ; Coronary vessels ; Cytokine Receptor Common beta Subunit - metabolism ; Growth factors ; Heart ; Heart Failure - therapy ; Hemodynamics ; Infections ; Laboratory animals ; Mesenchymal Stem Cell Transplantation - methods ; Mesenchymal Stem Cells - metabolism ; Mice ; Myocardial Ischemia - therapy ; Research Paper ; STAT5 Transcription Factor - metabolism ; Stem cells ; Stroke Volume ; Ventricular Function, Left</subject><ispartof>Theranostics, 2023-01, Vol.13 (6), p.1759-1773</ispartof><rights>The author(s).</rights><rights>2023. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The author(s) 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c407t-50c71b16c545b9ed18e40d2ce06254f4d9f0704b462750b9a1f83f70fd0d61903</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10091875/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10091875/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37064880$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Qi, Tingting</creatorcontrib><creatorcontrib>Xu, Xiaoming</creatorcontrib><creatorcontrib>Guo, Yongzhen</creatorcontrib><creatorcontrib>Xia, Yunlong</creatorcontrib><creatorcontrib>Peng, Lu</creatorcontrib><creatorcontrib>Li, Congye</creatorcontrib><creatorcontrib>Ding, Fengyue</creatorcontrib><creatorcontrib>Gao, Chao</creatorcontrib><creatorcontrib>Fan, Miaomiao</creatorcontrib><creatorcontrib>Yu, Min</creatorcontrib><creatorcontrib>Zhao, Huishou</creatorcontrib><creatorcontrib>He, Yuan</creatorcontrib><creatorcontrib>Li, Wenli</creatorcontrib><creatorcontrib>Hai, Chunxu</creatorcontrib><creatorcontrib>Gao, Erhe</creatorcontrib><creatorcontrib>Zhang, Xing</creatorcontrib><creatorcontrib>Gao, Feng</creatorcontrib><creatorcontrib>Fan, Yanhong</creatorcontrib><creatorcontrib>Yan, Wenjun</creatorcontrib><creatorcontrib>Tao, Ling</creatorcontrib><title>CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury</title><title>Theranostics</title><addtitle>Theranostics</addtitle><description>The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections. We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure.
Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice.
experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB.
We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependent STAT5/RNF4 activation.</description><subject>Adenoviruses</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Body fat</subject><subject>Cardiac function</subject><subject>Cardiovascular disease</subject><subject>Chemokines</subject><subject>Coronary vessels</subject><subject>Cytokine Receptor Common beta Subunit - metabolism</subject><subject>Growth factors</subject><subject>Heart</subject><subject>Heart Failure - therapy</subject><subject>Hemodynamics</subject><subject>Infections</subject><subject>Laboratory animals</subject><subject>Mesenchymal Stem Cell Transplantation - methods</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mice</subject><subject>Myocardial Ischemia - therapy</subject><subject>Research Paper</subject><subject>STAT5 Transcription Factor - metabolism</subject><subject>Stem cells</subject><subject>Stroke Volume</subject><subject>Ventricular Function, Left</subject><issn>1838-7640</issn><issn>1838-7640</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</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><recordid>eNpdkUtr3TAQhUVpaEKaTX9AEXRTCjcdybIlr0p7aZpAINDHWsjyKPbFtlxJvvT--8rNgzTazAz6ODOHQ8gbBueSlfAxdZM_V6woqhfkhKlCbWQl4OWT_picxbiD_ATwmtWvyHEhoRJKwQmZtz8u-Pcv1O8x4J85YIy9n-gc_OgTRpo6XIeENvV7pOhc7iL1jo4YcbLdYTQDjSnzuVochkjNremnmGgfbYdjb2mHJuRx2i3h8JocOTNEPLuvp-TXxdef28vN9c23q-3n640VINOmBCtZwypbirKpsWUKBbTcIlS8FE60tQMJohEVlyU0tWFOFU6Ca6GtWA3FKfl0pzsvzYitxSkFM-g59KMJB-1Nr___mfpO3_q9ZgA1U7LMCu_vFYL_vWBMesyOskMzoV-i5gq44FVZrsvePUN3fglT9qe5VDXnteQr9eGOssHHGNA9XsNAr2HqNUz9L8wMv316_yP6EF3xF3zSnGU</recordid><startdate>20230101</startdate><enddate>20230101</enddate><creator>Qi, Tingting</creator><creator>Xu, Xiaoming</creator><creator>Guo, Yongzhen</creator><creator>Xia, Yunlong</creator><creator>Peng, Lu</creator><creator>Li, Congye</creator><creator>Ding, Fengyue</creator><creator>Gao, Chao</creator><creator>Fan, Miaomiao</creator><creator>Yu, Min</creator><creator>Zhao, Huishou</creator><creator>He, Yuan</creator><creator>Li, Wenli</creator><creator>Hai, Chunxu</creator><creator>Gao, Erhe</creator><creator>Zhang, Xing</creator><creator>Gao, Feng</creator><creator>Fan, Yanhong</creator><creator>Yan, Wenjun</creator><creator>Tao, Ling</creator><general>Ivyspring International Publisher Pty Ltd</general><general>Ivyspring International Publisher</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>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20230101</creationdate><title>CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury</title><author>Qi, Tingting ; Xu, Xiaoming ; Guo, Yongzhen ; Xia, Yunlong ; Peng, Lu ; Li, Congye ; Ding, Fengyue ; Gao, Chao ; Fan, Miaomiao ; Yu, Min ; Zhao, Huishou ; He, Yuan ; Li, Wenli ; Hai, Chunxu ; Gao, Erhe ; Zhang, Xing ; Gao, Feng ; Fan, Yanhong ; Yan, Wenjun ; Tao, Ling</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c407t-50c71b16c545b9ed18e40d2ce06254f4d9f0704b462750b9a1f83f70fd0d61903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adenoviruses</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Body fat</topic><topic>Cardiac function</topic><topic>Cardiovascular disease</topic><topic>Chemokines</topic><topic>Coronary vessels</topic><topic>Cytokine Receptor Common beta Subunit - metabolism</topic><topic>Growth factors</topic><topic>Heart</topic><topic>Heart Failure - therapy</topic><topic>Hemodynamics</topic><topic>Infections</topic><topic>Laboratory animals</topic><topic>Mesenchymal Stem Cell Transplantation - methods</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Mice</topic><topic>Myocardial Ischemia - therapy</topic><topic>Research Paper</topic><topic>STAT5 Transcription Factor - metabolism</topic><topic>Stem cells</topic><topic>Stroke Volume</topic><topic>Ventricular Function, Left</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qi, Tingting</creatorcontrib><creatorcontrib>Xu, Xiaoming</creatorcontrib><creatorcontrib>Guo, Yongzhen</creatorcontrib><creatorcontrib>Xia, Yunlong</creatorcontrib><creatorcontrib>Peng, Lu</creatorcontrib><creatorcontrib>Li, Congye</creatorcontrib><creatorcontrib>Ding, Fengyue</creatorcontrib><creatorcontrib>Gao, Chao</creatorcontrib><creatorcontrib>Fan, Miaomiao</creatorcontrib><creatorcontrib>Yu, Min</creatorcontrib><creatorcontrib>Zhao, Huishou</creatorcontrib><creatorcontrib>He, Yuan</creatorcontrib><creatorcontrib>Li, Wenli</creatorcontrib><creatorcontrib>Hai, Chunxu</creatorcontrib><creatorcontrib>Gao, Erhe</creatorcontrib><creatorcontrib>Zhang, Xing</creatorcontrib><creatorcontrib>Gao, Feng</creatorcontrib><creatorcontrib>Fan, Yanhong</creatorcontrib><creatorcontrib>Yan, Wenjun</creatorcontrib><creatorcontrib>Tao, Ling</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Theranostics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qi, Tingting</au><au>Xu, Xiaoming</au><au>Guo, Yongzhen</au><au>Xia, Yunlong</au><au>Peng, Lu</au><au>Li, Congye</au><au>Ding, Fengyue</au><au>Gao, Chao</au><au>Fan, Miaomiao</au><au>Yu, Min</au><au>Zhao, Huishou</au><au>He, Yuan</au><au>Li, Wenli</au><au>Hai, Chunxu</au><au>Gao, Erhe</au><au>Zhang, Xing</au><au>Gao, Feng</au><au>Fan, Yanhong</au><au>Yan, Wenjun</au><au>Tao, Ling</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury</atitle><jtitle>Theranostics</jtitle><addtitle>Theranostics</addtitle><date>2023-01-01</date><risdate>2023</risdate><volume>13</volume><issue>6</issue><spage>1759</spage><epage>1773</epage><pages>1759-1773</pages><issn>1838-7640</issn><eissn>1838-7640</eissn><abstract>The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections. We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure.
Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice.
experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB.
We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependent STAT5/RNF4 activation.</abstract><cop>Australia</cop><pub>Ivyspring International Publisher Pty Ltd</pub><pmid>37064880</pmid><doi>10.7150/thno.81336</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenoviruses Animals Apoptosis Body fat Cardiac function Cardiovascular disease Chemokines Coronary vessels Cytokine Receptor Common beta Subunit - metabolism Growth factors Heart Heart Failure - therapy Hemodynamics Infections Laboratory animals Mesenchymal Stem Cell Transplantation - methods Mesenchymal Stem Cells - metabolism Mice Myocardial Ischemia - therapy Research Paper STAT5 Transcription Factor - metabolism Stem cells Stroke Volume Ventricular Function, Left |
| title | CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury |
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