Polysulfide nanoparticles inhibit fibroblast-to-myofibroblast transition via extracellular ROS scavenging and have potential anti-fibrotic properties

This paper is about the effects of reactive oxygen species (ROS) - and of their nanoparticle-mediated extracellular removal - in the TGF-I31-induced differentiation of fibroblasts (human dermal fibroblasts - HDFa) to more contractile myofibroblasts, and in the maintenance of this phenotype. Here, poly(propylene sulfide) (PPS) nanoparticles have been employed on 2D and 3D in vitro models, showing extremely low toxicity and undergoing negligible internalization, thereby ensuring an extracellular-only action. Firstly, PPS nanoparticles abrogated ROS-mediated downstream molecular events such as glutathione oxidation, NF-& kappa;B activation, and heme oxidase1 (HMOX) overexpression. Secondly, PPS nanoparticles were also capable to inhibit, prevent and reverse the TGF-I31-induced upregulation of key biomechanical elements, such as ED-a fibronectin (EF-A FN) and alphasmooth muscle actin (& alpha;-SMA), respectively markers of protomyofibroblastic and of myofibroblastic differentiation. We also confirmed that ROS alone are ineffective promoters of the myofibroblastic transition, although their presence contributes to its stabilization. Finally, the particles also countered TGF-I31-induced matrix- and tissuelevel phenomena, e.g., the upregulation of collagen type 1, the development of aberrant collagen type 1/3 ratios and the contracture of HDFa 3D-seeded fibrin constructs. In short, experimental data at molecular, cellular and tissue levels show a significant potential in the use of PPS nanoparticles as anti-fibrotic agents.

Automated summary

This paper investigates the effects of reactive oxygen species (ROS) and their removal through nanoparticle-mediated extracellular means on the differentiation of fibroblasts to myofibroblasts induced by TGF-I31. The results demonstrate that poly(propylene sulfide) (PPS) nanoparticles can inhibit ROS-mediated molecular events and prevent the upregulation of key biomechanical elements induced by TGF-I31, suggesting their potential as anti-fibrotic agents.