Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis.
OBJECTIVE
Hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis. However, their origin is still unknown. We tested the hypothesis that bone marrow (BM) contributes to the population of HSCs.


METHODS
Chimeric mice transplanted with donor BM from collagen alpha1(I)-GFP+ reporter mice were subjected to the bile duct ligation (BDL)-induced liver injury.


RESULTS
In response to injury, BM-derived collagen-expressing GFP+ cells were detected in liver tissues of chimeric mice. However, these cells were not activated HSCs in that they did not express alpha-smooth muscle actin or desmin and could not be isolated with the HSC fraction. Meanwhile, the majority of these BM-derived cells co-expressed collagen-GFP+ and CD45+, suggesting that these cells represent a unique population of fibrocytes. Consistent with their lymphoid origin, the number of GFP+CD45+ fibrocytes found in BM and spleen of chimeric mice increased in response to injury. Fibrocytes cultured in the presence of TGF-beta1 differentiated into SMA+desmin+ collagen-producing myofibroblasts, potentially contributing to liver fibrosis.


CONCLUSIONS
In response to the BDL-induced liver injury: (i) HSCs do not originate in the BM; (ii) collagen-producing fibrocytes are recruited from the BM to damaged liver.
Kisseleva
Tatiana
T
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. tk335@columbia.edu
Uchinami
Hiroshi
H
Feirt
Nikki
N
Quintana-Bustamante
Oscar
O
Segovia
Jose Carlos
JC
Schwabe
Robert F
RF
Brenner
David A
DA
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D024042:Collagen Type I; D003893:Desmin; D016212:Transforming Growth Factor beta; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens