title: Bone marrow transplantation improves hepatic fibrosis in Abcb4-/- mice via Th1 response and matrix metalloproteinase activity.
abstract: OBJECTIVE
  Reports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in Abcb4-/- mice. It is hypothesised that BM-Tx might have long-term therapeutic potential by altering the immunological and matrix remodelling processes leading to hepatic regeneration.
  
  
  METHODS
  After lethal irradiation of recipient mice, BM cells from GFP+ donor mice (allogeneic Tx) or Abcb4-/- mice (syngeneic Tx) were transplanted via tail vein injection. Readouts were performed 2, 10 and 20 weeks after Tx. Liver integrity was assessed serologically and histologically. Surrogate markers for fibrogenesis, T helper (Th) response, inflammation, graft-versus-host disease and fibrolysis were analysed by quantitative real-time PCR, zymography and immunohistology.
  
  
  RESULTS
  20 weeks after syngeneic and allogeneic BM-Tx, hepatic grading and staging were significantly improved. In contrast, 2 weeks after BM-Tx inflammatory grading, expression of inflammatory cell markers and associated chemokines and their receptors were increased and subsequently declined. In parallel, CD8+/GFP+ donor-derived T cells infiltrated the liver 2 weeks after BM-Tx. The Th1 cyokine interferon γ was increased 2 and 10 weeks after BM-Tx whereas the Th2 associated interleukin 13 was not altered. The gene expression of matrix metalloproteinases MMP-2, MMP-7, MMP-9 and MMP-13 was transiently upregulated and MMP-9 protein remained elevated 20 weeks after BM-Tx with enhanced gelatinase activity located within the fibrotic areas. Neutrophils were identified as major sources of MMP-9.
  
  
  CONCLUSIONS
  These results show that BM-Tx causes an antifibrotic Th1 response combined with transient inflammatory effects and subsequently upregulated MMP activity. Antifibrotic Th polarisation and prolonged proteolytic activity, especially of MMP-9, might be responsible for long-term amelioration of hepatic fibrosis.
authors.affiliation: Department of Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
authors.forename: Timo
authors.initials: T
authors.lastname: Rath
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Pasupuleti
authors.forename: Marc
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Caterina
authors.initials: C
authors.lastname: Neumann
authors.forename: Yuri
authors.initials: Y
authors.lastname: Churin
authors.forename: Christian
authors.initials: C
authors.lastname: Dierkes
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barth
authors.forename: Daniel
authors.initials: D
authors.lastname: Zahner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Graf
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018417:Th1 Cells / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018925:Chemokines; D016207:Cytokines; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D000097202:ATP-Binding Cassette Sub-Family B Member 4