Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury
Klotho is a protein primarily expressed in renal tubular epithelial cells. Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferatio...
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| Veröffentlicht in: | Cell biology international 2018-12, Vol.42 (12), p.1670-1679 |
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| creator | Zhang, Feng Wan, Xin Cao, Yi‐Zhi Sun, Dong Cao, Chang‐Chun |
| description | Klotho is a protein primarily expressed in renal tubular epithelial cells. Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferation ability and multidirectional differentiation ability and have been used to treat tissue injury. Thus, we hypothesized that Klotho expressed in BMSCs could increase the renal protective effects of BMSCs. To verify the hypothesis, we isolated BMSCs from C57BL/6 mice, transfected them with Klotho‐GFP‐adenovirus and investigated the change in BMSC proliferation. We then transplanted Klotho‐GFP‐BMSCs into mice with AKI and investigated the therapeutic effect compared with that of sham‐treated mice and GFP‐BMSC‐transplanted mice. Kidney fibrosis after ischemia/reperfusion injury (IRI) was relieved by BMSC transplantation, and the antifibrotic effect of BMSCs was significantly enhanced by overexpressing the Klotho gene. Mechanistic studies showed that Klotho increased pluripotency gene expression in BMSCs. Klotho produced by Klotho‐GFP‐BMSCs inhibited the Wnt/β‐catenin pathway in renal tubular epithelial cells (TECs). Klotho‐GFP‐BMSCs showed increased proliferative ability and more potent immuno‐regulation ability than did GFP‐BMSCs. Our findings suggested that Klotho gene‐modified BMSCs may be a better choice for cell therapy after AKI. |
| doi_str_mv | 10.1002/cbin.11068 |
| format | Article |
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Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferation ability and multidirectional differentiation ability and have been used to treat tissue injury. Thus, we hypothesized that Klotho expressed in BMSCs could increase the renal protective effects of BMSCs. To verify the hypothesis, we isolated BMSCs from C57BL/6 mice, transfected them with Klotho‐GFP‐adenovirus and investigated the change in BMSC proliferation. We then transplanted Klotho‐GFP‐BMSCs into mice with AKI and investigated the therapeutic effect compared with that of sham‐treated mice and GFP‐BMSC‐transplanted mice. Kidney fibrosis after ischemia/reperfusion injury (IRI) was relieved by BMSC transplantation, and the antifibrotic effect of BMSCs was significantly enhanced by overexpressing the Klotho gene. Mechanistic studies showed that Klotho increased pluripotency gene expression in BMSCs. Klotho produced by Klotho‐GFP‐BMSCs inhibited the Wnt/β‐catenin pathway in renal tubular epithelial cells (TECs). Klotho‐GFP‐BMSCs showed increased proliferative ability and more potent immuno‐regulation ability than did GFP‐BMSCs. Our findings suggested that Klotho gene‐modified BMSCs may be a better choice for cell therapy after AKI.</description><identifier>ISSN: 1065-6995</identifier><identifier>EISSN: 1095-8355</identifier><identifier>DOI: 10.1002/cbin.11068</identifier><identifier>PMID: 30358003</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Acute Kidney Injury - metabolism ; Acute Kidney Injury - pathology ; Acute Kidney Injury - physiopathology ; Acute Kidney Injury - therapy ; Animals ; Bone marrow ; bone marrow mesenchymal stem cells ; Catenin ; Cell Proliferation ; Coculture Techniques ; Epithelial cells ; Epithelial Cells - metabolism ; Epithelial Cells - pathology ; Epithelial-Mesenchymal Transition ; Fibrosis ; Gene expression ; Glucuronidase - genetics ; Ischemia ; ischemia‐reperfusion injury ; Kidney - metabolism ; Kidney - pathology ; Kidney - physiopathology ; kidney fibrosis ; Kidney Function Tests ; Kidney Tubules, Collecting - pathology ; Kidneys ; Klotho ; Klotho protein ; Macrophages - metabolism ; Macrophages - pathology ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal stem cells ; Mesenchymal Stem Cells - metabolism ; Mesenchyme ; Mice, Inbred C57BL ; Pluripotency ; Reperfusion ; Reperfusion Injury - metabolism ; Reperfusion Injury - pathology ; Reperfusion Injury - physiopathology ; Senescence ; Stem cell transplantation ; Wnt protein ; Wnt Signaling Pathway</subject><ispartof>Cell biology international, 2018-12, Vol.42 (12), p.1670-1679</ispartof><rights>2018 International Federation for Cell Biology</rights><rights>2018 International Federation for Cell Biology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3578-e0ff23bb1244f71418a2858bd2322d9841807a038b91cbcb6d3626cd4d2e99683</citedby><cites>FETCH-LOGICAL-c3578-e0ff23bb1244f71418a2858bd2322d9841807a038b91cbcb6d3626cd4d2e99683</cites><orcidid>0000-0001-7008-0673</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcbin.11068$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcbin.11068$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30358003$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Feng</creatorcontrib><creatorcontrib>Wan, Xin</creatorcontrib><creatorcontrib>Cao, Yi‐Zhi</creatorcontrib><creatorcontrib>Sun, Dong</creatorcontrib><creatorcontrib>Cao, Chang‐Chun</creatorcontrib><title>Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury</title><title>Cell biology international</title><addtitle>Cell Biol Int</addtitle><description>Klotho is a protein primarily expressed in renal tubular epithelial cells. Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferation ability and multidirectional differentiation ability and have been used to treat tissue injury. Thus, we hypothesized that Klotho expressed in BMSCs could increase the renal protective effects of BMSCs. To verify the hypothesis, we isolated BMSCs from C57BL/6 mice, transfected them with Klotho‐GFP‐adenovirus and investigated the change in BMSC proliferation. We then transplanted Klotho‐GFP‐BMSCs into mice with AKI and investigated the therapeutic effect compared with that of sham‐treated mice and GFP‐BMSC‐transplanted mice. Kidney fibrosis after ischemia/reperfusion injury (IRI) was relieved by BMSC transplantation, and the antifibrotic effect of BMSCs was significantly enhanced by overexpressing the Klotho gene. Mechanistic studies showed that Klotho increased pluripotency gene expression in BMSCs. Klotho produced by Klotho‐GFP‐BMSCs inhibited the Wnt/β‐catenin pathway in renal tubular epithelial cells (TECs). Klotho‐GFP‐BMSCs showed increased proliferative ability and more potent immuno‐regulation ability than did GFP‐BMSCs. Our findings suggested that Klotho gene‐modified BMSCs may be a better choice for cell therapy after AKI.</description><subject>Acute Kidney Injury - metabolism</subject><subject>Acute Kidney Injury - pathology</subject><subject>Acute Kidney Injury - physiopathology</subject><subject>Acute Kidney Injury - therapy</subject><subject>Animals</subject><subject>Bone marrow</subject><subject>bone marrow mesenchymal stem cells</subject><subject>Catenin</subject><subject>Cell Proliferation</subject><subject>Coculture Techniques</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - metabolism</subject><subject>Epithelial Cells - pathology</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Fibrosis</subject><subject>Gene expression</subject><subject>Glucuronidase - genetics</subject><subject>Ischemia</subject><subject>ischemia‐reperfusion injury</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidney - physiopathology</subject><subject>kidney fibrosis</subject><subject>Kidney Function Tests</subject><subject>Kidney Tubules, Collecting - pathology</subject><subject>Kidneys</subject><subject>Klotho</subject><subject>Klotho protein</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - pathology</subject><subject>Male</subject><subject>Mesenchymal Stem Cell Transplantation</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchyme</subject><subject>Mice, Inbred C57BL</subject><subject>Pluripotency</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - metabolism</subject><subject>Reperfusion Injury - pathology</subject><subject>Reperfusion Injury - physiopathology</subject><subject>Senescence</subject><subject>Stem cell transplantation</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway</subject><issn>1065-6995</issn><issn>1095-8355</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kbtuFDEUhkcIREKg4QGQJRqENIkv41lPSVZcIhIoAFGOfDnOeJm1F9vDajpqKp6FB-Eh8iTxZgMFBZWPjz9_Ojp_VT0m-JhgTE-0cv6YENyKO9UhwR2vBeP87q5ued12HT-oHqS0wpiQRrT3qwOGGRcYs8Pqx9sx5CGgS_Bw9f3nOhhnHRh0evFhmVAawrZcYIRvMpdC-lyeVQzZaQTWgs4JqRk5PzjlsvOXKA-APvt88vtX0enyyzuPNjIPW7nj0BdnPMwJSZshIqmnDKW9muL8sLpn5Zjg0e15VH169fLj8k19_v712fLFea0ZX4gasLWUKUVo09gFaYiQVHChDGWUmk6UBl5IzITqiFZatYa1tNWmMRS6rhXsqHq2925i-DpByv3aJQ3jKD2EKfWUUE67sh5c0Kf_oKswRV-mKxQrrkVDeaGe7ykdQ0oRbL-Jbi3j3BPc7xLqdwn1NwkV-MmtclJrMH_RP5EUgOyBrRth_o-qX56evdtLrwEg856R</recordid><startdate>201812</startdate><enddate>201812</enddate><creator>Zhang, Feng</creator><creator>Wan, Xin</creator><creator>Cao, Yi‐Zhi</creator><creator>Sun, Dong</creator><creator>Cao, Chang‐Chun</creator><general>Wiley Subscription Services, Inc</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>7QR</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7008-0673</orcidid></search><sort><creationdate>201812</creationdate><title>Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury</title><author>Zhang, Feng ; Wan, Xin ; Cao, Yi‐Zhi ; Sun, Dong ; Cao, Chang‐Chun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3578-e0ff23bb1244f71418a2858bd2322d9841807a038b91cbcb6d3626cd4d2e99683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acute Kidney Injury - metabolism</topic><topic>Acute Kidney Injury - pathology</topic><topic>Acute Kidney Injury - physiopathology</topic><topic>Acute Kidney Injury - therapy</topic><topic>Animals</topic><topic>Bone marrow</topic><topic>bone marrow mesenchymal stem cells</topic><topic>Catenin</topic><topic>Cell Proliferation</topic><topic>Coculture Techniques</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - metabolism</topic><topic>Epithelial Cells - pathology</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Fibrosis</topic><topic>Gene expression</topic><topic>Glucuronidase - genetics</topic><topic>Ischemia</topic><topic>ischemia‐reperfusion injury</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidney - physiopathology</topic><topic>kidney fibrosis</topic><topic>Kidney Function Tests</topic><topic>Kidney Tubules, Collecting - pathology</topic><topic>Kidneys</topic><topic>Klotho</topic><topic>Klotho protein</topic><topic>Macrophages - metabolism</topic><topic>Macrophages - pathology</topic><topic>Male</topic><topic>Mesenchymal Stem Cell Transplantation</topic><topic>Mesenchymal stem cells</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Mesenchyme</topic><topic>Mice, Inbred C57BL</topic><topic>Pluripotency</topic><topic>Reperfusion</topic><topic>Reperfusion Injury - metabolism</topic><topic>Reperfusion Injury - pathology</topic><topic>Reperfusion Injury - physiopathology</topic><topic>Senescence</topic><topic>Stem cell transplantation</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Feng</creatorcontrib><creatorcontrib>Wan, Xin</creatorcontrib><creatorcontrib>Cao, Yi‐Zhi</creatorcontrib><creatorcontrib>Sun, Dong</creatorcontrib><creatorcontrib>Cao, Chang‐Chun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell biology international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Feng</au><au>Wan, Xin</au><au>Cao, Yi‐Zhi</au><au>Sun, Dong</au><au>Cao, Chang‐Chun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury</atitle><jtitle>Cell biology international</jtitle><addtitle>Cell Biol Int</addtitle><date>2018-12</date><risdate>2018</risdate><volume>42</volume><issue>12</issue><spage>1670</spage><epage>1679</epage><pages>1670-1679</pages><issn>1065-6995</issn><eissn>1095-8355</eissn><abstract>Klotho is a protein primarily expressed in renal tubular epithelial cells. Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferation ability and multidirectional differentiation ability and have been used to treat tissue injury. Thus, we hypothesized that Klotho expressed in BMSCs could increase the renal protective effects of BMSCs. To verify the hypothesis, we isolated BMSCs from C57BL/6 mice, transfected them with Klotho‐GFP‐adenovirus and investigated the change in BMSC proliferation. We then transplanted Klotho‐GFP‐BMSCs into mice with AKI and investigated the therapeutic effect compared with that of sham‐treated mice and GFP‐BMSC‐transplanted mice. Kidney fibrosis after ischemia/reperfusion injury (IRI) was relieved by BMSC transplantation, and the antifibrotic effect of BMSCs was significantly enhanced by overexpressing the Klotho gene. Mechanistic studies showed that Klotho increased pluripotency gene expression in BMSCs. Klotho produced by Klotho‐GFP‐BMSCs inhibited the Wnt/β‐catenin pathway in renal tubular epithelial cells (TECs). Klotho‐GFP‐BMSCs showed increased proliferative ability and more potent immuno‐regulation ability than did GFP‐BMSCs. Our findings suggested that Klotho gene‐modified BMSCs may be a better choice for cell therapy after AKI.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30358003</pmid><doi>10.1002/cbin.11068</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-7008-0673</orcidid></addata></record> |
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| subjects | Acute Kidney Injury - metabolism Acute Kidney Injury - pathology Acute Kidney Injury - physiopathology Acute Kidney Injury - therapy Animals Bone marrow bone marrow mesenchymal stem cells Catenin Cell Proliferation Coculture Techniques Epithelial cells Epithelial Cells - metabolism Epithelial Cells - pathology Epithelial-Mesenchymal Transition Fibrosis Gene expression Glucuronidase - genetics Ischemia ischemia‐reperfusion injury Kidney - metabolism Kidney - pathology Kidney - physiopathology kidney fibrosis Kidney Function Tests Kidney Tubules, Collecting - pathology Kidneys Klotho Klotho protein Macrophages - metabolism Macrophages - pathology Male Mesenchymal Stem Cell Transplantation Mesenchymal stem cells Mesenchymal Stem Cells - metabolism Mesenchyme Mice, Inbred C57BL Pluripotency Reperfusion Reperfusion Injury - metabolism Reperfusion Injury - pathology Reperfusion Injury - physiopathology Senescence Stem cell transplantation Wnt protein Wnt Signaling Pathway |
| title | Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury |
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