The cellular sources of collagen in normal rat liver have been examined. Hepatocytes and nonparenchymal (sinusoidal) cells were isolated and established in primary monolayer culture. These cells were incubated with radiolabeled proline in the presence of L-ascorbate and p-aminopropionitrile. Nondialyzable material was prepared from the cell layer and the medium from each type of culture. The level of collagen accumulation was determined by measuring labeled hydroxyproline and sensitivity to purified bacterial collagenase. In hepatocytes, collagen represented 0.2% of both secreted and cell-associated labeled protein. In sinusoidal cells, collagen was 3.2% of secreted and 1.1% of cell-associated proteins. The total secreted labeled collagen, expressed per microgram of DNA, was similar in hepatocytes and sinusoidal cells. However cell-associated collagen in hepatocyte culture was approximately 10-fold that present in sinusoidal cells. These findings indicate that, while collagen formation is a relatively important function of sinusoidal cells, in normal liver the contribution of hepatocytes to total hepatic collagen accumulation may be substantial.
Collagen is present in normal liver around vascular structures including sinusoids, as revealed by a "reticulin" stain of fixed tissue. By comparison with pathologic fibrosis, collagen is sparse in normal liver and previously was given little attention. Recent studies with cells in culture suggest a prominent role for collagen in the modulation of specific cell function, raising the possibility that this matrix component plays an important role not only in pathologic states but also in the normal tissue (1).
Immunohistochemical studies with specific anticollagen antibodies reveal that liver contains at least three distinct collagen types, each with a characteristic lobular distribution (2). This suggests that more than one cell type in the liver may be involved in the production and secretion of collagen. The cellular sources of hepatic collagen are speculative. The prevailing assumption is that hepatic mesenchymal (sinusoidal) cells are solely responsible for the elaboration of collagen, by extrapo-