Matrix as a Modulator of Hepatic Fibrogenesis

Abstract

The extracellular matrix (ECM) provides cells with positional information and a mechanical scaffold for adhesion and migration. It consists of collagens, glycoproteins, proteoglycans, glycosaminoglycans and molecules that are bound specifically by the ECM, such as certain growth factors/cytokines, matrix metalloproteinases (MMPs) and processing enzymes such as tissue transglutaminase and procollagen propeptidases. This finely tuned ecosystem is dysbalanced in chronic fibrogenesis, which can be regarded as a continuous wound-healing process and which results in scar formation. Importantly, the ECM directs cellular differentiation, migration, proliferation, and fibrogenic activation or deactivation. Partially via defined oligopeptide sequences or structural domains, the ECM transfers specific signals to cells that act in concert with growth factors/cytokines. These signals either confer stress activation, with a resultant fibrogenic response, or stress relaxation, with a fibrolytic response. Alternatively, ECM-derived peptides can modulate angiogenesis, or growth factor and MMP availability and activity. Current ECM-related antifibrotic strategies are based on the identification and in vivo application of ECM-derived biomodulatory peptides, peptide sequences, or their nonpeptidic mimetics. The latter open the opportunity of oral application and an extended biological half-life. Examples are peptides derived from collagens VI (stress activation) and XIV (stress relaxation), or collagenous consensus peptides that remove ECM-bound MMPs and growth factors. Furthermore, certain peptides can be used as targeting structures to the fibrogenic lesion.

Hepatocyte Transplantation Activates Hepatic Stellate Cells With Beneficial Modulation of Cell Engraftment in the Rat *

“…During the initial phase of ischemic liver injury, Kupffer cell activation, phagocytic infiltration, and stimulation of sinusoidal endothelial cells, multiple soluble factors and cytokines with HSC-activating properties are released. [6][7][8] Initiation of HSC activation should promote an early matrix-degrading phenotype. The uPA-plasmin system induces pro-MMPs during early remodeling in liver regeneration, 7,35 and expression of plasmin-activating uPA, as well as its inhibitor, PAI-1, is upregulated immediately after cell transplantation.…”

“…The hepatic stellate cell (HSC) represents an attractive candidate for this consideration. [6][7][8] HSC are located in the space of Disse, which transplanted cells must circumvent during translocation from liver sinusoids to the parenchyma. 1 HSC regulate multiple physiological processes in the liver, including extracellular matrix (ECM) deposition during the onset, as well as regression, of hepatic fibrosis.…”

“…6 Activation of HSC causes multiple early events, including gene regulation and release of soluble factors. [6][7][8] Other changes include HSC proliferation and increased desmin or ␣-smooth muscle actin (SMA) expression, when HSC undergo myofibroblast-like change.…”

“…[1][2][3][4][5] Using DPPIVϪ rats, we demonstrate here that hepatocyte transplantation partially activated HSC, including expression of growth factors and ECM-modifying matrix metalloproteinases (MMPs), which are largely produced in HSC. 7,8 Moreover, depletion of HSC interfered with cell engraftment.…”

Advances in alcoholic liver disease

“…Fibrosis is characterized by deposition of ECM. The main ECM to accumulate is collagen type I, but other ECM proteins also accumulate during fibrogenesis, such as laminin, fibronectin, and fibrin(ogen) [82]. The major cell type that contributes to fibrogenesis is the activated hepatic stellate cell; however, other cellular origins of myofibroblast-like cells are becoming increasingly recognized, such as peri-portal fibroblasts, fibrocytes, and transdifferentiated epithelia [83][84][85][86].…”