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Bone marrow transplantation demonstrates medullar origin of CD34 + fibrocytes and ameliorates hepatic fibrosis in Abcb4 −/− mice
Author(s) -
Roderfeld Martin,
Rath Timo,
Voswinckel Robert,
Dierkes Christian,
Dietrich Hartmut,
Zahner Daniel,
Graf Jürgen,
Roeb Elke
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23274
Subject(s) - fibrocyte , cd34 , pathology , bone marrow transplantation , fibrosis , bone marrow , hepatic fibrosis , medicine , cancer research , transplantation , chemistry , microbiology and biotechnology , stem cell , biology
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 (α‐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 α‐SMA + /CRP2 + phenotype were expressed in ≈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. (H EPATOLOGY 2009.)