Seminar

Osteopontin, Ductular Reaction and Fibrosis

Aritz Lopategi, PhD

Fibrogenesis, or activation of the wound-healing response to persistent liver injury, is characterized by changes in the composition and quantity of extracellular matrix (ECM) deposits distorting the normal hepatic architecture by forming fibrotic scars. Failure to degrade accumulated ECM is a major reason why fibrosis progresses to cirrhosis. Emerging antifibrogenic therapies aim at inhibiting the activation of profibrogenic cells to prevent fibrillar Collagen-I deposition, degrading excessive ECM to recover normal liver architecture and restoring functional liver mass. While in normal liver, replacement of necrotic and apoptotic hepatocytes occurs by replication of quiescent adjacent hepatocytes within the lobule, when periportal hepatocytes are damaged and their division is impaired, a pool of OC arises acting as a secondary proliferative pathway. OC are bipotential cells residing primarily in the periportal region, when the liver parenchyma is damaged, OC become a source of regenerating hepatocytes, BEC and draining ductules in order to restore the functional liver mass. A by-product from the activation of this alternative proliferative pathway is the so-called ductular reaction (DR), a reactive lesion at the portal tract interface comprising small biliary ductules with the associated stroma, bile plugs and inflammatory cells. Proliferating BEC are a source of molecules that activate extracellular matrix (ECM) deposition and secrete pro-inflammatory and chemotactic cytokines, which attract and activate Hepatic stellate cells (HSC) and portal fibroblasts. These and other, yet to be discovered mediators, elicit the fibrogenic response and contribute to the progression of liver fibrosis. Although different cell types contribute to the increase in fibrillar Collagen-I during hepatic fibrogenesis, they all undergo a common process of differentiation and acquisition of a classical myofibroblast-like phenotype. HSCs are considered central ECM-producing cells within the injured liver, playing a significant role in Collagen-I deposition. In the healthy liver, they reside in the sinusoidal space of Disse; however, during chronic injury, they activate while acquiring motile, proinflammatory and profibrogenic properties. Activated HSCs migrate and accumulate at the sites of tissue repair, secreting large amounts of ECM, mostly Collagen-I and regulating ECM remodeling. Up-regulation of fibrillar Collagen-I is thus a key event leading to scarring, the pathophysiological hallmark of liver fibrosis. Though some current therapies have proven beneficial, dissecting key profibrogenic mechanisms, pathways and mediators of disease progression is vital. Several studies have identified osteopontin (OPN) as significantly up-regulated during liver injury and in HSCs. OPN is a soluble cytokine and a matrix bound protein that can remain intracellular or be secreted, hence allowing autocrine and paracrine signaling. OPN, as a matricellular phosphoglycoprotein, functions as an adaptor and modulator of cell-matrix interactions. Among its many roles, it regulates cell migration, ECM invasion and cell adhesion resulting from its ability to bind integrins and CD44. OPN expression increases in tumorigenesis, angiogenesis and in response to inflammation, cellular stress and injury. OPN plays an important role in regulating tissue remodeling and cell survival as well as in chemoattracting inflammatory cells. In this presentation we show how OPN emerges as a key cytokine within the ECM protein network driving the increase in Collagen-I protein contributing to scarring and liver fibrosis. And the contribution of OPN to the HSC profibrogenic behavior and the molecular mechanisms and signaling pathways involved in governing Collagen-I protein expression during the fibrogenic response to liver injury.