The role of miRNAs in stress-responsive hepatic stellate cells during liver fibrosis

Abstract

The progression of liver fibrosis and cirrhosis is associated with the persistence of an injury causing agent, leading to changes in the extracellular environment and a disruption of the cellular homeostasis of liver resident cells. Recruitment of inflammatory cells, apoptosis of hepatocytes, and changes in liver microvasculature are some examples of changing cellular environment that lead to the induction of stress responses in nearby cells. During liver fibrosis, the major stresses include hypoxia, oxidative stress, and endoplasmic reticulum stress. When hepatic stellate cells (HSCs) are subjected to such stress, they modulate fibrosis progression by induction of their activation toward a myofibroblastic phenotype, or by undergoing apoptosis, and thus helping fibrosis resolution. It is widely accepted that microRNAs are import regulators of gene expression, both during normal cellular homeostasis, as well as in pathologic conditions. MicroRNAs are short RNA sequences that regulate the gene expression by mRNA destabilization and inhibition of mRNA translation. Specific microRNAs have been identified to play a role in the activation process of HSCs on the one hand and in stress-responsive pathways on the other hand in other cell types (Table 2). However, so far there are no reports for the involvement of miRNAs in the different stress responses linked to HSC activation. Here, we review briefly the major stress response pathways and propose several miRNAs to be regulated by these stress responsive pathways in activating HSCs, and discuss their potential specific pro-or anti-fibrotic characteristics.

miR-706 inhibits the oxidative stress-induced activation of PKCα/TAOK1 in liver fibrogenesis

“…Previous studies have shown that hepatocytes and HSCs are the main intrinsic cell sources which contribute to the development of liver fibrosis458. To further clarify the biological roles of miR-706 in hepatic fibrosis, we performed in situ hybridization (ISH).…”

“…Activated fibroblasts are characterized by their contractile capacity, the deposition of ECM and subsequently the production of hepatic fibrosis38. HSCs are regarded as the main source of fibroblasts4. Moreover, profibrogenic fibroblasts can also originate from portal fibroblasts, bone marrow stem cells and hepatocytes undergoing EMT678.…”

“…Hepatic stellate cells (HSCs) are the major source of activated fibroblasts45. Moreover, recent studies have shown that activated HSCs , portal fibroblasts , and myofibroblasts of bone-marrow origin have fibrogenic properties67.…”

Az idült májbetegségek progressziójához vezető folyamatok

“…Gének kifejeződését szabá-lyozzák poszttranszkripcionálisan. A csillagsejtek aktivá-lódásában szerepet játszanak a miR-29, a miR-146 és a miR-16 mikro-RNS-ek [49]. HCV-fertőzésben a miR-122 részt vesz a vírus stabilitásában és propagációjában [50][51][52].…”

Extended-criteria donors in liver transplantation Part II: reviewing the impact of extended-criteria donors on the complications and outcomes of liver transplantation

“…When hepatic stellate cells (HSCs) are subjected to stress such as hypoxia, oxidative stress or endoplasmic reticulum stress, they modulate fibrosis progression by induction of their activation toward a myofibroblastic phenotype, or by undergoing apoptosis, and thus helping fibrosis resolution [103]. General inflammation pathways also lead to liver fibrosis.…”