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Roderfeld M, Rath T, Voswinckel R, Dierkes C, Dietrich H, Zahner D, Graf J, Roeb E: Bone marrow transplantation demonstrates medullar origin of CD34+ fibrocytes and ameliorates hepatic fibrosis in Abcb4-/- mice. Hepatology. 2010 Jan;51(1):267-76.
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. |
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