Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis
Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) h...
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| Veröffentlicht in: | Physiological genomics 2017-10, Vol.49 (10), p.541-548 |
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| creator | Xu, Junwang Zgheib, Carlos Hodges, Maggie M Caskey, Robert C Hu, Junyi Liechty, Kenneth W |
| description | Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP-9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression. |
| doi_str_mv | 10.1152/physiolgenomics.00090.2016 |
| format | Article |
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Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP-9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression.</description><identifier>ISSN: 1094-8341</identifier><identifier>EISSN: 1531-2267</identifier><identifier>DOI: 10.1152/physiolgenomics.00090.2016</identifier><identifier>PMID: 28842435</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animal models ; Animals ; Coculture Techniques ; Collagen ; Collagen (type I) ; Collagen Type I - metabolism ; Collagen Type III - metabolism ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - physiopathology ; Extracellular matrix ; Extracellular Matrix Proteins - metabolism ; Female ; Fibroblasts ; Fibroblasts - cytology ; Gelatinase B ; Gene expression ; Gene Expression Regulation ; Matrix metalloproteinase ; Matrix Metalloproteinase 9 - genetics ; Matrix Metalloproteinase 9 - metabolism ; Matrix protein ; Mesenchymal Stem Cell Transplantation - methods ; Mesenchymal stem cells ; Mesenchymal Stromal Cells - cytology ; Mesenchyme ; Metalloproteinase ; Mice, Transgenic ; MicroRNAs - genetics ; miRNA ; Proteins ; Proteolysis ; Skin ; Stem cell transplantation ; Stem cells ; Wound healing ; Wound Healing - physiology</subject><ispartof>Physiological genomics, 2017-10, Vol.49 (10), p.541-548</ispartof><rights>Copyright © 2017 the American Physiological Society.</rights><rights>Copyright American Physiological Society Oct 2017</rights><rights>Copyright © 2017 the American Physiological Society 2017 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-133d212b99ae364f1882ba93c27eeda8e0b9e8ce00e22f659f5725836f34c1303</citedby><cites>FETCH-LOGICAL-c454t-133d212b99ae364f1882ba93c27eeda8e0b9e8ce00e22f659f5725836f34c1303</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28842435$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Junwang</creatorcontrib><creatorcontrib>Zgheib, Carlos</creatorcontrib><creatorcontrib>Hodges, Maggie M</creatorcontrib><creatorcontrib>Caskey, Robert C</creatorcontrib><creatorcontrib>Hu, Junyi</creatorcontrib><creatorcontrib>Liechty, Kenneth W</creatorcontrib><title>Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis</title><title>Physiological genomics</title><addtitle>Physiol Genomics</addtitle><description>Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP-9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression.</description><subject>Animal models</subject><subject>Animals</subject><subject>Coculture Techniques</subject><subject>Collagen</subject><subject>Collagen (type I)</subject><subject>Collagen Type I - metabolism</subject><subject>Collagen Type III - metabolism</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - physiopathology</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix Proteins - metabolism</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Gelatinase B</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 9 - genetics</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Matrix protein</subject><subject>Mesenchymal Stem Cell Transplantation - methods</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stromal Cells - cytology</subject><subject>Mesenchyme</subject><subject>Metalloproteinase</subject><subject>Mice, Transgenic</subject><subject>MicroRNAs - genetics</subject><subject>miRNA</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Skin</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Wound healing</subject><subject>Wound Healing - physiology</subject><issn>1094-8341</issn><issn>1531-2267</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtP3DAUha0KVB7tX6issmGTwe-xWSChEbSVGLGhu0qW49zMGCVxaiet5t-TwBQVVrZ1zz33XH8IfaVkQalkF_12l0NsNtDFNvi8IIQYsmCEqg_omEpOC8bU8mC6EyMKzQU9Qic5PxJCxVLLj-iIaS2Y4PIY_VpDhs5vd61rcB6gxR6aJmMfUwI_4ND2LiSocBVcCUPw-G8cuwpvwTWh2-ByhyvwCVyeXzerNe5THCA2U8T8CR3WrsnweX-eop-3Nw-r78Xd_bcfq-u7wgsphoJyXjHKSmMccCVqqjUrneGeLQEqp4GUBrQHQoCxWklTyyWTmquaC0854afo6sW3H8sWKg_dkFxj-xRal3Y2umDfVrqwtZv4x0qltBJmMjjfG6T4e4Q82Dbk-SNcB3HMlhrONDeGzLPO3kkf45i6ab1JZRjTREkxqS5fVD7FnBPUr2EosTNE-w6ifYZoZ4hT85f_13lt_UeNPwGfUp9V</recordid><startdate>20171001</startdate><enddate>20171001</enddate><creator>Xu, Junwang</creator><creator>Zgheib, Carlos</creator><creator>Hodges, Maggie M</creator><creator>Caskey, Robert C</creator><creator>Hu, Junyi</creator><creator>Liechty, Kenneth W</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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20171001</creationdate><title>Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis</title><author>Xu, Junwang ; Zgheib, Carlos ; Hodges, Maggie M ; Caskey, Robert C ; Hu, Junyi ; Liechty, Kenneth W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-133d212b99ae364f1882ba93c27eeda8e0b9e8ce00e22f659f5725836f34c1303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Coculture Techniques</topic><topic>Collagen</topic><topic>Collagen (type I)</topic><topic>Collagen Type I - metabolism</topic><topic>Collagen Type III - metabolism</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - physiopathology</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix Proteins - metabolism</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Gelatinase B</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 9 - genetics</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Matrix protein</topic><topic>Mesenchymal Stem Cell Transplantation - methods</topic><topic>Mesenchymal stem cells</topic><topic>Mesenchymal Stromal Cells - cytology</topic><topic>Mesenchyme</topic><topic>Metalloproteinase</topic><topic>Mice, Transgenic</topic><topic>MicroRNAs - genetics</topic><topic>miRNA</topic><topic>Proteins</topic><topic>Proteolysis</topic><topic>Skin</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Wound healing</topic><topic>Wound Healing - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Junwang</creatorcontrib><creatorcontrib>Zgheib, Carlos</creatorcontrib><creatorcontrib>Hodges, Maggie M</creatorcontrib><creatorcontrib>Caskey, Robert C</creatorcontrib><creatorcontrib>Hu, Junyi</creatorcontrib><creatorcontrib>Liechty, Kenneth W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Physiological genomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Junwang</au><au>Zgheib, Carlos</au><au>Hodges, Maggie M</au><au>Caskey, Robert C</au><au>Hu, Junyi</au><au>Liechty, Kenneth W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis</atitle><jtitle>Physiological genomics</jtitle><addtitle>Physiol Genomics</addtitle><date>2017-10-01</date><risdate>2017</risdate><volume>49</volume><issue>10</issue><spage>541</spage><epage>548</epage><pages>541-548</pages><issn>1094-8341</issn><eissn>1531-2267</eissn><abstract>Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP-9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>28842435</pmid><doi>10.1152/physiolgenomics.00090.2016</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Animals Coculture Techniques Collagen Collagen (type I) Collagen Type I - metabolism Collagen Type III - metabolism Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - physiopathology Extracellular matrix Extracellular Matrix Proteins - metabolism Female Fibroblasts Fibroblasts - cytology Gelatinase B Gene expression Gene Expression Regulation Matrix metalloproteinase Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - metabolism Matrix protein Mesenchymal Stem Cell Transplantation - methods Mesenchymal stem cells Mesenchymal Stromal Cells - cytology Mesenchyme Metalloproteinase Mice, Transgenic MicroRNAs - genetics miRNA Proteins Proteolysis Skin Stem cell transplantation Stem cells Wound healing Wound Healing - physiology |
| title | Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis |
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