{"title":"在Atp7b-/-小鼠模型威尔逊氏病肝脏再生与骨髓来源的肌成纤维细胞或炎症细胞，而不是肝细胞是有害的。","authors":"Yogeshwar Sharma, Jinghua Liu, Kathleen E Kristian, Antonia Follenzi, Sanjeev Gupta","doi":"10.3727/105221618X15320123457380","DOIUrl":null,"url":null,"abstract":"In Wilson's disease, Atp7b mutations impair copper excretion with liver or brain damage. Healthy transplanted hepatocytes repopulate the liver, excrete copper, and reverse hepatic damage in animal models of Wilson's disease. In Fah-/- mice with tyrosinemia and α-1 antitrypsin mutant mice, liver disease is resolved by expansions of healthy hepatocytes derived from transplanted healthy bone marrow stem cells. This potential of stem cells has not been defined for Wilson's disease. In diseased Atp7b-/- mice, we reconstituted bone marrow with donor cells expressing green fluorescent protein reporter from healthy transgenic mice. Mature hepatocytes originating from donor bone marrow were identified by immunostaining for green fluorescence protein and bile canalicular marker, dipeptidylpeptidase-4. Mesenchymal and inflammatory cell markers were used for other cells from donor bone marrow cells. Gene expression, liver tests, and tissues were analyzed for outcomes in Atp7b-/- mice. After bone marrow transplantation in Atp7b-/- mice, donor-derived hepatocytes containing bile canaliculi appeared within weeks. Despite this maturity, donor-derived hepatocytes neither divided nor expanded. The liver of Atp7b-/- mice was not repopulated by donor-derived hepatocytes: Atp7b mRNA remained undetectable; liver tests, copper content, and fibrosis actually worsened. Restriction of proliferation in hepatocytes accompanied oxidative DNA damage. By contrast, donor-derived mesenchymal and inflammatory cells extensively proliferated. These contributed to fibrogenesis through greater expression of inflammatory cytokines. In Wilson's disease, donor bone marrow-derived cells underwent different fates: hepatocytes failed to proliferate; inflammatory cells proliferated to worsen disease outcomes. This will help guide stem cell therapies for conditions with proinflammatory or profibrogenic microenvironments.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"19 1","pages":"15-24"},"PeriodicalIF":0.0000,"publicationDate":"2018-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15320123457380","citationCount":"1","resultStr":"{\"title\":\"In <i>Atp7b</i><sup><i>-/-</i></sup> Mice Modeling Wilson's Disease Liver Repopulation With Bone Marrow-Derived Myofibroblasts or Inflammatory Cells and Not Hepatocytes Is Deleterious.\",\"authors\":\"Yogeshwar Sharma, Jinghua Liu, Kathleen E Kristian, Antonia Follenzi, Sanjeev Gupta\",\"doi\":\"10.3727/105221618X15320123457380\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"In Wilson's disease, Atp7b mutations impair copper excretion with liver or brain damage. Healthy transplanted hepatocytes repopulate the liver, excrete copper, and reverse hepatic damage in animal models of Wilson's disease. In Fah-/- mice with tyrosinemia and α-1 antitrypsin mutant mice, liver disease is resolved by expansions of healthy hepatocytes derived from transplanted healthy bone marrow stem cells. This potential of stem cells has not been defined for Wilson's disease. In diseased Atp7b-/- mice, we reconstituted bone marrow with donor cells expressing green fluorescent protein reporter from healthy transgenic mice. Mature hepatocytes originating from donor bone marrow were identified by immunostaining for green fluorescence protein and bile canalicular marker, dipeptidylpeptidase-4. Mesenchymal and inflammatory cell markers were used for other cells from donor bone marrow cells. Gene expression, liver tests, and tissues were analyzed for outcomes in Atp7b-/- mice. After bone marrow transplantation in Atp7b-/- mice, donor-derived hepatocytes containing bile canaliculi appeared within weeks. Despite this maturity, donor-derived hepatocytes neither divided nor expanded. The liver of Atp7b-/- mice was not repopulated by donor-derived hepatocytes: Atp7b mRNA remained undetectable; liver tests, copper content, and fibrosis actually worsened. Restriction of proliferation in hepatocytes accompanied oxidative DNA damage. By contrast, donor-derived mesenchymal and inflammatory cells extensively proliferated. These contributed to fibrogenesis through greater expression of inflammatory cytokines. In Wilson's disease, donor bone marrow-derived cells underwent different fates: hepatocytes failed to proliferate; inflammatory cells proliferated to worsen disease outcomes. This will help guide stem cell therapies for conditions with proinflammatory or profibrogenic microenvironments.\",\"PeriodicalId\":12502,\"journal\":{\"name\":\"Gene expression\",\"volume\":\"19 1\",\"pages\":\"15-24\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2018-12-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.3727/105221618X15320123457380\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gene expression\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3727/105221618X15320123457380\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2018/7/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene expression","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3727/105221618X15320123457380","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2018/7/20 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
In Atp7b-/- Mice Modeling Wilson's Disease Liver Repopulation With Bone Marrow-Derived Myofibroblasts or Inflammatory Cells and Not Hepatocytes Is Deleterious.
In Wilson's disease, Atp7b mutations impair copper excretion with liver or brain damage. Healthy transplanted hepatocytes repopulate the liver, excrete copper, and reverse hepatic damage in animal models of Wilson's disease. In Fah-/- mice with tyrosinemia and α-1 antitrypsin mutant mice, liver disease is resolved by expansions of healthy hepatocytes derived from transplanted healthy bone marrow stem cells. This potential of stem cells has not been defined for Wilson's disease. In diseased Atp7b-/- mice, we reconstituted bone marrow with donor cells expressing green fluorescent protein reporter from healthy transgenic mice. Mature hepatocytes originating from donor bone marrow were identified by immunostaining for green fluorescence protein and bile canalicular marker, dipeptidylpeptidase-4. Mesenchymal and inflammatory cell markers were used for other cells from donor bone marrow cells. Gene expression, liver tests, and tissues were analyzed for outcomes in Atp7b-/- mice. After bone marrow transplantation in Atp7b-/- mice, donor-derived hepatocytes containing bile canaliculi appeared within weeks. Despite this maturity, donor-derived hepatocytes neither divided nor expanded. The liver of Atp7b-/- mice was not repopulated by donor-derived hepatocytes: Atp7b mRNA remained undetectable; liver tests, copper content, and fibrosis actually worsened. Restriction of proliferation in hepatocytes accompanied oxidative DNA damage. By contrast, donor-derived mesenchymal and inflammatory cells extensively proliferated. These contributed to fibrogenesis through greater expression of inflammatory cytokines. In Wilson's disease, donor bone marrow-derived cells underwent different fates: hepatocytes failed to proliferate; inflammatory cells proliferated to worsen disease outcomes. This will help guide stem cell therapies for conditions with proinflammatory or profibrogenic microenvironments.
期刊介绍：
Gene Expression, The Journal of Liver Research will publish articles in all aspects of hepatology. Hepatology, as a research discipline, has seen unprecedented growth especially in the cellular and molecular mechanisms of hepatic health and disease, which continues to have a major impact on understanding liver development, stem cells, carcinogenesis, tissue engineering, injury, repair, regeneration, immunology, metabolism, fibrosis, and transplantation. Continued research and improved understanding in these areas will have a meaningful impact on liver disease prevention, diagnosis, and treatment. The existing journal Gene Expression has expanded its focus to become Gene Expression, The Journal of Liver Research to meet this growing demand. In its revised and expanded scope, the journal will publish high-impact original articles, reviews, short but complete articles, and special articles (editorials, commentaries, opinions) on all aspects of hepatology, making it a unique and invaluable resource for readers interested in this field. The expanded team, led by an Editor-in-Chief who is uniquely qualified and a renowned expert, along with a dynamic and functional editorial board, is determined to make this a premier journal in the field of hepatology.
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