A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis.
OBJECTIVE
Myofibroblasts of bone marrow origin have recently been found in a number of parenchymal organs such as the gut and kidney. We have analyzed the origin of myofibroblasts within fibrotic liver in 2 scenarios: (1) 7 male patients (hepatitis B; hepatitis B and D; Wilson's disease; hepatitis B, D, and C; and 3 with hepatitis C) who received liver transplants from female donors and subsequently developed liver fibrosis and (2) a female patient who received a bone marrow transplant from a male donor and subsequently developed hepatitis C-induced cirrhosis.


METHODS
Through the use of in situ hybridization for the Y chromosome, we have tracked male cells of extrahepatic origin. The phenotype of these male cells was examined by immunohistochemistry using a panel of antibodies against alpha-smooth muscle actin (alpha SMA), vimentin, fibulin-2, and leukocyte common antigen (CD45). Confocal microscopy was performed to confirm the location of the Y chromosome probe within the myofibroblast nuclei.


RESULTS
Significant numbers of Y chromosome-positive cells in fibrotic areas were found to be positive for alpha-SMA, vimentin, and fibulin-2 and negative for CD45, thus having a myofibroblast phenotype. In the liver transplant cases, 6.8%-22.2% of alpha-SMA-positive myofibroblasts contained the Y chromosome. In the female recipient of a bone marrow transplant from a male donor, 12.4% of the myofibroblasts were Y chromosome positive, indicating a bone marrow origin.


CONCLUSIONS
There is a significant contribution to liver cirrhosis in humans from extrahepatically derived myofibroblasts in liver disease of diverse etiology.
Forbes
Stuart J
SJ
Hepatology Section, Department of Medicine, Imperial College, London, England. s.j.forbes@imperial.ac.uk
Russo
Francesco P
FP
Rey
Virginia
V
Burra
Patrizia
P
Rugge
Massimo
M
Wright
Nicholas A
NA
Alison
Malcolm R
MR
D000199:Actins / Q000032:analysis; D000328:Adult; D001706:Biopsy; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins / Q000032:analysis; D041322:Chromosomes, Human, Y; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology* / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged
D000199:Actins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C084612:fibulin 2; D017493:Leukocyte Common Antigens