About this Research Topic
Myofibroblasts (MFB) are present in many tissues but they are studied primarily because of the important role they play in tissue repair. They are able to contract the wound and fill the wound gap with newly synthesized connective tissue. They actively participate in extracellular matrix (ECM) remodeling. The main source of MFB in liver are quiescent hepatic stellate cells (HSC) and portal fibroblasts. MFB accumulate in liver in various pathological conditions; in liver fibrosis of various origin, in liver tumors, in the course of defined genetic disorders and in liver infected with parasites. MFB differentiation from their precursors is a key event in fibrosis initiation. It is a complex proces that among other factors involves changes in composition and mechanical resistance of surrounding ECM and the action of cytokines. The persistence of MFB in fibrotic septa is connected with the irreversibility of liver cirrhosis. This project will be aimed at various pathways leading to functional MFB.
Potential contributors should concentrate on these events occurring in the process of MFB differentiation:
1) epigenetic mechanisms that modify gene expression in HSC but are not due to changes in primary DNA sequence:
- DNA methylation (adding methyl groups to cytosine in CpG islands in gene promoter regions)
- changes in the spectrum of microRNAs
- histone modification (acetylation and methylation)
- regulation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and the switch from the expression of adipogenic genes to that of myogenic genes in HSC
2) Notch signaling
3) Hedgehog signaling
4) the differences in the action of cytokines on MFB compared to that on HSC
5) the role of cell environment including substrate rigidity and three-dimensional (3D) ECM
Potential contributors will be selected to cover all these aspects of myofibroblast biology.
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