In Atp7b−/− mice modeling Wilson's disease liver repopulation with bone marrow-derived myofibroblasts or inflammatory cells and not hepatocytes is deleterious

Yogeshwar Sharma, Jinghua Liu, Kathleen E. Kristian, Antonia Follenzi, Sanjeev Gupta

Research output: Contribution to journalArticle

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 a-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.

Original languageEnglish (US)
Pages (from-to)15-24
Number of pages10
JournalGene expression
Volume19
Issue number1
DOIs
StatePublished - 2018

Keywords

  • Bone marrow transplantation
  • Cell therapy
  • Copper
  • Differentiation
  • Stem cells

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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