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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents



ID: 559687.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Bone marrow transplantation demonstrates medullar origin of CD34+ fibrocytes and ameliorates hepatic fibrosis in Abcb4-/- mice
Authors:Roderfeld, M.; Rath, T.; Voswinckel, R.; Dierkes, C.; Dietrich, H.; Zahner, D.; Graf, J.; Roeb, E.
Title of Journal:Hepatology
Volume:51
Issue / Number:1
Start Page:267
End Page:76
Audience:Not Specified
Abstract / Description:Bone marrow (BM)-derived stem cells and CD34(+) fibrocytes are associated with fibrogenesis in several organs. In an Abcb4(-/-) mouse model for sclerosing cholangitis alpha-smooth muscle actin-positive (alpha-SMA(+)) myofibroblasts are thought to play a pivotal role in hepatic fibrogenesis. The aim of this study was 2-fold: (1) to demonstrate that the origin of an important fibrogenetic cell population is the BM; and (2) to investigate whether transplantation of BM (BM-Tx) affects liver function, staging, and grading. Surrogate markers for fibrogenesis and regulation of hepatic stellate cells (HSC) as well as progenitor-cell-derived fibrocytes in liver tissue were analyzed by quantitative real-time polymerase chain reaction (PCR) and immunohistology. After lethal irradiation of recipient mice, BM-Tx was carried out by way of tail vein injection of BM cells from marker protein donors (green fluorescent protein, GFP(+)) or Abcb4(-/-) mice as control (syngeneic Tx). Parameters of liver function were assessed serologically and histologically. Activated HSC of alpha-SMA(+)/CRP2(+) phenotype were expressed in approximately 50% of proliferating bile ducts, whereas fibrotic liver parenchyma showed no expression thereof. Epithelial mesenchymal transfer (EMT) was visualized in the areas of proliferating bile ducts. The hematopoietic origin of CD34(+) fibrocytes was demonstrated immunohistologically in livers of BM chimeric mice. These CD34(+) cells infiltrated hepatic lobules from portal fields and developed a desmin(+) phenotype expressing collagen type I in fibrotic parenchyma as well as in vitro after isolation by magnetic cell separation. Transplantation of GFP(+)/Abcb4(+) BM improved liver function and staging compared with sham transplantation, but no significant differences were noticed among allogeneic and syngeneic Tx. CONCLUSION: The present study is the first to identify that both BM-derived fibrocytes and HSC are involved in biliary fibrogenesis in Abcb4(-/-) mice. Our data suggest that changes in immunity subsequent to BM-Tx may alter hepatic fibrosis.
Free Keywords:Animals; Antigens, CD34/*metabolism; *Bone Marrow Transplantation; Cell Differentiation; Cholangitis, Sclerosing/*pathology/physiopathology; Collagen Type I/biosynthesis; Desmin/biosynthesis; Fibroblasts/*pathology; Liver Cirrhosis/pathology/*therapy; Mice; Mice, Inbred BALB C; Mice, Knockout; P-Glycoproteins/*deficiency
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.
Identifiers:ISSN:1527-3350 (Electronic) 0270-9139 (Linking)
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=..
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