Bone marrow transplantation demonstrates medullar origin of CD34+ fibrocytes and ameliorates hepatic fibrosis in Abcb4-/- mice.
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.


CONCLUSIONS
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.
Roderfeld
Martin
M
Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.
Rath
Timo
T
Voswinckel
Robert
R
Dierkes
Christian
C
Dietrich
Hartmut
H
Zahner
Daniel
D
Graf
Jürgen
J
Roeb
Elke
E
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D015209:Cholangitis, Sclerosing / Q000473:pathology* / Q000503:physiopathology; D024042:Collagen Type I / Q000096:biosynthesis; D003893:Desmin / Q000096:biosynthesis; D005347:Fibroblasts / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018952:Antigens, CD34; D024042:Collagen Type I; D003893:Desmin; D000097202:ATP-Binding Cassette Sub-Family B Member 4