Peripheral blood mononuclear cells acquire myofibroblast characteristics in granulation tissue.

BACKGROUND: Bone marrow-derived cell populations possess progenitor cell capacities. Emerging evidence also suggests significant plasticity of differentiated mononuclear cell lineages. We therefore assessed the distribution of transplanted peripheral blood mononuclear cells (PBMCs) in granulation tissue formation, and evaluated their possible transdifferentiation into myofibroblasts. METHODS: Silastic tubes were inserted into the peritoneal cavity of rats, followed by injection of PKH26-labelled PBMCs isolated from donor animals. At 3, 14 and 21 days, the distribution of PKH26(+) cells as well as their colocalization with myofibroblast/smooth muscle cell [alpha-smooth muscle (alpha-SM) actin] or macrophage markers (ED1/ED2) were determined. RESULTS: Round-shaped PKH26(+) cells accumulated around the implants at 3 days, while myofibroblasts were rare. Later, peritoneal granulation tissue constituted an inner, multilayered capsule primarily comprising alpha-SM actin(+) cells that was surrounded by more loosely organized inflammatory connective tissue. PKH26-labelled, spindle-shaped cells were abundantly found in tissue capsules. As a key finding, granulation tissue at 14 and 21 days contained cells with both PKH26 and alpha-SM actin labelling. Accordingly, a subpopulation of cells staining positive for macrophage markers showed a spindle-shaped morphology and alpha-SM actin expression. CONCLUSIONS: Transplanted PBMCs contribute to granulation tissue, and acquire myofibroblast characteristics during de novo tissue formation. Mononuclear cells may transdifferentiate into myofibroblast-like cells within an inflammatory environment.

Decreased factor VIII levels during acetaminophen-induced murine fulminant hepatic failure.

During human fulminant hepatic failure (FHF) circulating levels of most hemostatic proteins fall dramatically. Concurrently, factor VIII (fVIII) procoagulant activity rises despite destruction of the hepatocytes considered responsible for fVIII synthesis. This observation suggests a role for cells other than hepatocytes in fVIII biosynthesis during FHF. We have attempted to identify nonhepatocytic sites of fVIII biosynthesis by inducing FHF in mice using acetaminophen overdose, a common cause of human FHF. Acetaminophen-treated mice consistently displayed signs characteristic of FHF, including elevated plasma aminotransferase activity. However, acetaminophen-treated mice demonstrated markedly reduced fVIII activity, contrary to the observation in human FHF. von Willebrand factor antigen levels were only mildly reduced, suggesting that the decrease in fVIII is not secondary to loss of von Willebrand factor. These results imply that there are fundamental differences in the regulation of plasma fVIII levels between humans and mice.