A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis

Gastroenterology. 2004 Apr;126(4):955-63. doi: 10.1053/j.gastro.2004.02.025.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Adult
  • Biopsy
  • Bone Marrow Cells / cytology*
  • Bone Marrow Transplantation
  • Calcium-Binding Proteins / analysis
  • Chromosomes, Human, Y
  • Extracellular Matrix Proteins / analysis
  • Female
  • Fibroblasts / chemistry
  • Fibroblasts / pathology*
  • Humans
  • Leukocyte Common Antigens / analysis
  • Liver / pathology
  • Liver Cirrhosis / pathology*
  • Liver Cirrhosis / surgery
  • Liver Transplantation
  • Male
  • Middle Aged

Substances

  • Actins
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • fibulin 2
  • Leukocyte Common Antigens