HSCs play a distinct role in different phases of oval cell‐mediated liver regeneration

Abstract

Hepatic stem cell niche plays an important role in hepatic oval cell-mediated liver regeneration. As a component of hepatic stem cell niche, the role of hepatic stellate cells (HSCs) in oval cell proliferation needs further studies. In the present study, we isolated HSCs from rats at indicated time point after partial hepatectomy (PH) in 2-acetylaminofluorene/PH oval cell proliferation model. Conditional medium (CM) from HSCs were collected to detect their effects on proliferation and the mitogen-activated protein kinase pathway activation of two oval cell lines. We found that CM collected from HSCs at early phase of liver regeneration (4 and 9 days group) contained high levels of hepatocyte growth factor (HGF) and stimulated oval cell proliferation via extracellular signal-regulated kinase and p38 pathway. CM collected from HSCs at terminal phase of liver regeneration (12 and 15 days group) contained high levels of transforming growth factor (TGF)-β1, which suppressed DNA synthesis of oval cells. The shift between these two distinct effects depended on the balance between HGF and TGF-β1 secreted by HSCs. Our study demonstrated that HSCs acted as a positive regulator at the early phase and a negative regulator at the terminal phase of the oval cell-mediated liver regeneration.

Hepatic stellate cells in liver development, regeneration, and cancer

“…2 and summarized in Figure 3). Conditioned media collected from hepatic stellate cells harvested from rats during early liver regeneration following 2AAF/PH injury contain high levels of HGF and promote oval cell proliferation (82). One potential mediator of HGF production by hepatic stellate cells is the neurotrophin receptor P75 NTR , which is expressed in human hepatic stellate cells following fibrotic liver injury.…”

“…As mentioned earlier, conditioned medium collected from hepatic stellate cells at early phases of liver regeneration in a 2AAF/PH injury model contains high levels of HGF. This strong mitogen may override the antiproliferative effect of TGF-β1 (82). In contrast, at terminal phases of liver regeneration, hepatic stellate cells produce high levels of TGF-β1, which inhibits hepatocyte proliferation and even induces apoptosis.…”

Pericytes in Vascular Development and Function

“…The liver can fully regenerate within a matter of weeks if up to two-thirds of the hepatic mass is removed. Stellate cells are thought to play important roles at multiple stages of liver regeneration, including positive regulators of early-phase cell proliferation and negative regulators of the later phase [147]. This is based on the observation that inhibiting activated stellate cells either with gliotoxin or L-cysteine prevents normal regeneration [148,149].…”

Stellate Cells in Alcoholic Hepatitis

“…HSCs also contribute to the homeostatic maintenance of the three-dimensional architecture of liver by regulating the turnover of extracellular matrix (ECM) in the healthy liver [11]. HSCs are also involved in the regulation of liver regeneration through cell-to-cell interactions and cytokine networks [12], modulation of sinusoidal blood flow [13], and contribute to hepatic immune tolerance via their immunological properties [14] (see Chapter 14). HSCs have a complex secretome, including growth factors, prostaglandins, cytokines, and apolipoproteins; all these factors contribute to the homeostasis of ECM [5,15].…”