Typing of hepatic nonparenchymal cells using fibulin-2 and cytoglobin/STAP as liver fibrogenesis-related markers

Fibulin-2 and cytoglobin/stellate cell activation-associated protein (Cygb/STAP) are considered to be markers of hepatic myofibroblasts (MFs) and stellate cells (HSCs), respectively. The aim of the present study was to characterize the nonparenchymal cells (NPCs) of normal rat livers and carbon tetrachloride-induced fibrotic rat livers with respect to the expression of these two proteins. NPCs in normal (Glissons capsules) and fibrotic (fibrotic septa) connective tissues were immunohistochemically categorized into four cell types in terms of the expression of fibulin-2 and Cygb/STAP: fibulin-2 and Cygb/STAP double-positive (Fib⁺/STAP⁺); fibulin-2-positive and Cygb/STAP-negative (Fib⁺/STAP^–); Fib^–/STAP⁺; and Fib^–/STAP^–. The Glissons capsules had Fib⁺/STAP⁺ and Fib^–/STAP^– cell occupancy rates of 45.5% and 54.5%, respectively, but did not contain Fib⁺/STAP^– or Fib^–/STAP⁺ cells. On the other hand, the fibrotic septa contained Fib⁺/STAP⁺, Fib^–/STAP⁺, and Fib^–/STAP^– cells at occupancy rates of 35.0%, 50.5%, and 9.1%, respectively, but did not contain Fib⁺/STAP^– cells. Thus, fibrosis is characterized by a dramatic increase in Fib^–/STAP⁺ NPCs, and a dramatic decrease in Fib^–/STAP^– NPCs. Fib⁺/STAP⁺ NPCs are located uniformly in Glissons capsules and peripherally in fibrotic septa. The present study strongly suggests that Fib⁺/STAP⁺ and Fib^–/STAP⁺ NPCs correspond to MFs and activated HSCs, respectively, both of which may contribute to liver fibrogenesis.