Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow–derived cells
Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone‐marrow–deri...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2014-05, Vol.59 (5), p.1816-1829 |
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| creator | Nagaishi, Kanna Ataka, Koji Echizen, Eijiro Arimura, Yoshiaki Fujimiya, Mineko |
| description | Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone‐marrow–derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone‐marrow (BM)‐derived MSCs were administered to high‐fat diet (HFD)‐induced type 2 diabetic mice and streptozotocin (STZ)‐induced insulin‐deficient diabetic mice. MSC‐conditioned medium (MSC‐CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM‐chimeric mice. Curative effects of MSC and MSC‐CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD‐diabetic mice and persistent hyperglycemia in STZ‐diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD‐ and STZ‐diabetic mice. In addition to inducing hepatocyte regeneration in STZ‐diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD‐diabetic mice. Conclusion: MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs. (Hepatology 2014;59:1816–1829) |
| doi_str_mv | 10.1002/hep.26975 |
| format | Article |
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In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone‐marrow–derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone‐marrow (BM)‐derived MSCs were administered to high‐fat diet (HFD)‐induced type 2 diabetic mice and streptozotocin (STZ)‐induced insulin‐deficient diabetic mice. MSC‐conditioned medium (MSC‐CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM‐chimeric mice. Curative effects of MSC and MSC‐CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD‐diabetic mice and persistent hyperglycemia in STZ‐diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD‐ and STZ‐diabetic mice. In addition to inducing hepatocyte regeneration in STZ‐diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD‐diabetic mice. Conclusion: MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs. (Hepatology 2014;59:1816–1829)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.26975</identifier><identifier>PMID: 24375439</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Animals ; Apoptosis ; Bone marrow ; Bone Marrow Cells - physiology ; Cell Communication ; Cell Differentiation ; Cell Lineage ; Cell Movement ; Cytokines - analysis ; Diabetes ; Diabetes Mellitus, Experimental - pathology ; Diabetes Mellitus, Experimental - therapy ; Diet, High-Fat ; Hepatology ; Insulin Resistance ; Liver - metabolism ; Liver - pathology ; Mesenchymal Stem Cell Transplantation ; Mice ; Mice, Inbred C57BL ; Rats ; Rodents ; Streptozocin</subject><ispartof>Hepatology (Baltimore, Md.), 2014-05, Vol.59 (5), p.1816-1829</ispartof><rights>2014 by the American Association for the Study of Liver Diseases</rights><rights>2014 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4535-f7c0f3ea3a32419f7549ad9ae09a560a0ad33735868067d12889a11f864708183</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.26975$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.26975$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24375439$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nagaishi, Kanna</creatorcontrib><creatorcontrib>Ataka, Koji</creatorcontrib><creatorcontrib>Echizen, Eijiro</creatorcontrib><creatorcontrib>Arimura, Yoshiaki</creatorcontrib><creatorcontrib>Fujimiya, Mineko</creatorcontrib><title>Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow–derived cells</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone‐marrow–derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone‐marrow (BM)‐derived MSCs were administered to high‐fat diet (HFD)‐induced type 2 diabetic mice and streptozotocin (STZ)‐induced insulin‐deficient diabetic mice. MSC‐conditioned medium (MSC‐CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM‐chimeric mice. Curative effects of MSC and MSC‐CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD‐diabetic mice and persistent hyperglycemia in STZ‐diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD‐ and STZ‐diabetic mice. In addition to inducing hepatocyte regeneration in STZ‐diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD‐diabetic mice. Conclusion: MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs. (Hepatology 2014;59:1816–1829)</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Bone marrow</subject><subject>Bone Marrow Cells - physiology</subject><subject>Cell Communication</subject><subject>Cell Differentiation</subject><subject>Cell Lineage</subject><subject>Cell Movement</subject><subject>Cytokines - analysis</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes Mellitus, Experimental - therapy</subject><subject>Diet, High-Fat</subject><subject>Hepatology</subject><subject>Insulin Resistance</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Mesenchymal Stem Cell Transplantation</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Rats</subject><subject>Rodents</subject><subject>Streptozocin</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9O3DAQxi1UBNuFQ1-gstQLl4D_xLF9rFa0VKKCA5yjSTLZNUribewF5dYTL9A35EnwLtseuHQu80n-zYxnPkI-cXbOGRMXK1yfi8JqdUBmXAmdSanYBzJjQrPMcmmPyccQHhhjNhfmiByLXGqVSzsjzz8x4FCvph46GiL2tMauo3GFI6wnCj12zo8QMdDGQYXR1TSNg-jrKSJtoIclUjfQ3tVIqynJlatcdMMyydZ1MRU7P1Df0soPSHsYR__08vtPg6N7xGY3L5yQwxa6gKf7PCf33y7vFlfZ9c33H4uv11mdK6myVteslQgSpMi5bdMSFhoLyCyoggGDRkotlSkMK3TDhTEWOG9NkWtmuJFzcvbWdz36XxsMsexd2P4ABvSbUHKtixTa2P-jiltRcKOLhH55hz74zTikRbaUUTLFtuHnPbWpemzK9ejSMabyrxkJuHgDnlyH0793zsqty2U6e7lzuby6vN0J-QqBspqp</recordid><startdate>201405</startdate><enddate>201405</enddate><creator>Nagaishi, Kanna</creator><creator>Ataka, Koji</creator><creator>Echizen, Eijiro</creator><creator>Arimura, Yoshiaki</creator><creator>Fujimiya, Mineko</creator><general>Wolters Kluwer Health, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201405</creationdate><title>Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow–derived cells</title><author>Nagaishi, Kanna ; Ataka, Koji ; Echizen, Eijiro ; Arimura, Yoshiaki ; Fujimiya, Mineko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4535-f7c0f3ea3a32419f7549ad9ae09a560a0ad33735868067d12889a11f864708183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Bone marrow</topic><topic>Bone Marrow Cells - physiology</topic><topic>Cell Communication</topic><topic>Cell Differentiation</topic><topic>Cell Lineage</topic><topic>Cell Movement</topic><topic>Cytokines - analysis</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes Mellitus, Experimental - therapy</topic><topic>Diet, High-Fat</topic><topic>Hepatology</topic><topic>Insulin Resistance</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Mesenchymal Stem Cell Transplantation</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Rats</topic><topic>Rodents</topic><topic>Streptozocin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagaishi, Kanna</creatorcontrib><creatorcontrib>Ataka, Koji</creatorcontrib><creatorcontrib>Echizen, Eijiro</creatorcontrib><creatorcontrib>Arimura, Yoshiaki</creatorcontrib><creatorcontrib>Fujimiya, Mineko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagaishi, Kanna</au><au>Ataka, Koji</au><au>Echizen, Eijiro</au><au>Arimura, Yoshiaki</au><au>Fujimiya, Mineko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow–derived cells</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2014-05</date><risdate>2014</risdate><volume>59</volume><issue>5</issue><spage>1816</spage><epage>1829</epage><pages>1816-1829</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone‐marrow–derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone‐marrow (BM)‐derived MSCs were administered to high‐fat diet (HFD)‐induced type 2 diabetic mice and streptozotocin (STZ)‐induced insulin‐deficient diabetic mice. MSC‐conditioned medium (MSC‐CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM‐chimeric mice. Curative effects of MSC and MSC‐CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD‐diabetic mice and persistent hyperglycemia in STZ‐diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD‐ and STZ‐diabetic mice. In addition to inducing hepatocyte regeneration in STZ‐diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD‐diabetic mice. Conclusion: MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs. (Hepatology 2014;59:1816–1829)</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>24375439</pmid><doi>10.1002/hep.26975</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Bone marrow Bone Marrow Cells - physiology Cell Communication Cell Differentiation Cell Lineage Cell Movement Cytokines - analysis Diabetes Diabetes Mellitus, Experimental - pathology Diabetes Mellitus, Experimental - therapy Diet, High-Fat Hepatology Insulin Resistance Liver - metabolism Liver - pathology Mesenchymal Stem Cell Transplantation Mice Mice, Inbred C57BL Rats Rodents Streptozocin |
| title | Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow–derived cells |
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