The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies

Abstract

Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts, and deposition of extracellular matrix (ECM). Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes) to the injured liver. Hepatic macrophages (Kupffer cells) produce TGFβ1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGFβ1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident hepatic stellate cells and portal fibroblasts are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g., stop collagen production and partially restore expression of lipogenic genes). Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases) and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

“…The progression of liver fibrosis is promoted by oxidative stress [12,13], although this is likely to be just one of multiple processes involved. In the present study, oxidative stress in the liver of octn1 -/-was much greater than that in wild-type mice at 1 and 2 weeks after treatment with DMN (Fig.…”

“…In particular, hepatic stellate cells (HSCs) are activated by oxidative stress to collagen-producing myofibroblasts, which promote liver fibrosis by producing ECM [12,13]. Oxidative stress may also injure parenchymal cells, leading to further 6 progression of liver injury.…”

“…Total RNA was extracted according to the standard ISOGEN procedure (Nippon Gene, Toyama, Japan) and used for cDNA synthesis with oligo (dT) [12][13][14][15][16][17][18] …”

Myofibroblasts in Normal and Fibrotic Liver in Different Animal Species

“…MFs are capable of expressing a variety of cytoskeletal proteins which are used as markers of their differentiation. MFs contain microfi lament bundles and/or stress fi bers in the cytoplasm which play an important role in the mechanism of contraction that is similar to the mechanism of contraction of smooth-muscle cells [10][11][12].…”

T Helper 2 Cytokine Signaling in Bone Marrow–Derived Fibroblasts

“…2 Recent studies have shown that myofibroblasts consist of heterogeneous cells, which are derived from different kinds of cells, such as resident fibroblasts, pericytes, epithelial/ endothelial mesenchymal transition-derived cells, and bone marrow-derived fibroblasts (termed fibrocytes). 3,4 Of these cells, accumulating evidence suggest that bone marrow-derived fibroblasts are significantly involved in the pathogenesis of renal fibrosis through (1) recruitment into kidney and (2) differentiation into myofibroblasts. 3 Bone marrow-derived fibroblasts were first identified in the wound chamber model by Bucala et al 5 Bone marrow-derived fibroblasts comprise a minor fraction of the circulating pool of leukocytes (,1%) and share the markers of hematopoietic cells, such as CD45, CD11b, and CD34, as well as mesenchymal cells, including type I collagen (COLI), fibronectin, and platelet-derived growth factor receptor-b.…”