Activation of stem cells in hepatic diseases

Abstract

The liver has enormous regenerative capacity. Following acute liver injury, hepatocyte division regenerates the parenchyma but, if this capacity is overwhelmed during massive or chronic liver injury, the intrinsic hepatic progenitor cells (HPCs) termed oval cells are activated. These HPCs are bipotential and can regenerate both biliary epithelia and hepatocytes. Multiple signalling pathways contribute to the complex mechanism controlling the behaviour of the HPCs. These signals are delivered primarily by the surrounding microenvironment. During liver disease, stem cells extrinsic to the liver are activated and bone-marrow-derived cells play a role in the generation of fibrosis during liver injury and its resolution. Here, we review our current understanding of the role of stem cells during liver disease and their mechanisms of activation.

Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver

“…4B). This finding is consistent with either an inflammatory response or an oval cell response, both of which occur following liver injury in situations where hepatocyte proliferation is attenuated (14)(15)(16). To explore this possibility further at the transcriptional level, we determined the relative expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α, Fig.…”

“…The histological appearance and presence of an abundant oval cell response in mst1/2 double mutant liver tissue are suggestive of a response to chronic liver damage (16). This observation is of particular interest for several reasons.…”

Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells

“…1 During chronic liver injury, however, when the functional liver mass is reduced and coincidentally hepatocyte proliferation is wholly or partly impaired, liver regeneration is facilitated by a compartment of dynamic, heterogeneous liver progenitor cells (LPCs), 2 which in rodents are often called oval cells. LPCs are rarely detected in healthy tissue, but once activated, they proliferate and migrate into the parenchyma and differentiate into either cholangiocytes or hepatocytes.…”

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

“…5 LPC have been of increasing interest in latest years since they could have a role not only in regeneration but also in fibrogenesis and carcinogenesis. 6 In experimental models and various human liver diseases, LPC expand in close proximity to a-smooth muscle actin (aSMA)-positive cells deriving from either sinusoidal hepatic stellate cells (HSC) or portal fibroblasts depending upon the location of the injury in the lobule. 2,7 There are increasing data demonstrating an intimate cross-talk between LPC and aSMA-positive myofibroblasts 3,[8][9][10][11] and several studies in rodent models and human diseases have pointed out a strong relationship between severity of fibrosis and intensity of the ductular reaction.…”

“…On the opposite, activation of HSC or portal fibroblasts into myofibroblasts producing extracellular matrix (ECM) and growth factors precedes LPC expansion and differentiation in periportal regions along a porto-venous axis. 6,11 Recently, it has been shown that inhibition of HSC activation greatly diminished LPC expansion. 19 Therefore, HSC or portal fibroblast activation seems a prerequisite for LPC expansion, as already demonstrated in other stem cell niches.…”