Fat-storing cells and myofibroblasts are involved in the initial phase of carbon tetrachloride-induced hepatic fibrosis in BN/BiRij rats.
This study on the appearance, distribution and kinetics of fibroblast-like cells (fat-storing cells, transitional cells, myofibroblasts and fibroblasts) after CCl4-treatment was undertaken to delineate further the respective roles of these cell types in liver fibrogenesis. The different cell types were distinguished on the basis of their immunophenotypic pattern with a combination of marker antibodies and on the basis of ultrastructural characteristics. Combined staining for alpha-smooth muscle actin (sma) and desmin (Des) revealed perisinusoidal fat-storing cells (FSC) as d+ sma- and myofibroblasts around the central veins of the normal rat liver as d+ sma+. During the initial phase of CCl4-induced hepatic fibrosis (week 1 and 2), the number of d+ sma+ cells increased in the degenerating area around the central veins and d+ sma+ cells appeared in the very thin fibrotic septa at week 2. Ultrastructural examination of the affected central areas showed the presence of myofibroblasts. These sma+ cells proliferated, as shown by double staining for bromodeoxyuridine (BrdU) and sma. In degenerating parenchymal areas, d+ sma- FSC were present. The FSC in the perisinusoidal space of areas which were not affected by CCl4 intoxification, remained d+ sma-. These immunostaining findings support the electron microscopical results, which show the presence of cells with the typical ultrastructural characteristics of FSC in both the degenerating areas and the perisinusoidal space of unaffected areas. After one week of CCl4-treatment, enhanced deposition of procollagen type III was observed around the central veins. Enhanced deposition of collagen type IV was seen subendothelially along the sinusoids, notably in degenerating parenchymal areas where the septa were later formed. FSC appear to be the principal source of collagen type IV during fibrogenesis. These observations further support and specify the role of FSC in early fibrogenesis. With the progression of the CCl4-induced fibrosis, d+ sma+ myofibroblasts remained localized in the fibrotic septa, but now along their outer edge. The majority of the cells in the septa were formed by d- sma- cells indicating a prominent role of fibroblasts in the septal formation. Septal fibroblasts are not only likely to produce matrix components, but also were shown to degrade collagen, as evidenced by the increased number of collagen-containing vacuoles during the course of fibrosis. In conclusion, myofibroblasts and FSC appear to be the main cell types involved in the initial phase of liver fibrogenesis induced by CCl4. Both myofibroblasts and FSC divide and transform.(ABSTRACT TRUNCATED AT 400 WORDS)
Seifert
W F
WF
Institute for Vascular Disease and Aging (IVVO-TNO), Leiden, The Netherlands.
Roholl
P J
PJ
Blauw
B
B
van der Ham
F
F
van Thiel-De Ruiter
C F
CF
Seifert-Bock
I
I
Bosma
A
A
Knook
D L
DL
Brouwer
A
A
D000818:Animals; D002251:Carbon Tetrachloride; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008854:Microscopy, Electron; D051381:Rats; D011914:Rats, Inbred BN
D003094:Collagen; D002251:Carbon Tetrachloride