Understanding how MSCs reverse radiation-induced fibrosis: HGF vs. TGF-B1

Abstract

Radiation induced fibrosis (RIF) can be understood as a form of chronic radiation-induced bystander effect (RIBE). It is a fibrotic process different than acute radiation syndrome (ARS), which is an inflammatory process that has different mediators and effector cells. It is triggered by Reactive Oxygen Species (ROS) activation of the matrix-embedded L-TGF-β complex. TGF-β acts by directing cellular processes that culminate in a fibrotic state. These include epithelial and endothelial mesenchymal transition (EMT and EnMT), G1 phase growth arrest, stimulation of fibrosis, and apoptosis, characterized by hypocellularity with a predominance of fibrocytes and myofibroblasts, fibrosis, and variable loss of tissue function. Fat grafting is the only clinically available tool to reverse RIF. The reversal of RIF is mediated by the mesenchymal stem cells (MSCs) embedded in the stromal vascular fraction (SVF) adipose tissue. The mechanism of action is the release of HGF (hepatocyte growth factor) by the MSCs into the surrounding RIF tissue. The HGF initiates a “mitotic growth program” that reprograms cell behavior. These changes include EMT and EnMT, stimulation of cell proliferation and morphogenesis, anti-apoptosis, downregulation of TGF-β, dissolution of fibrosis, and cell motility. The “mitotic growth program” culminates in tissue regeneration and reversal of RIF.

Keywords

HGF / TGF-β / RIF / radiation-induced fibrosis / fat grafting / MSC

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