**4. Perspective**

Novel findings obtained imply that fibronectin regulates the balance between active and inactive (latent) TGF-β, which in turn modulates ECM production and remodeling following injury, and consequently retains adult tissue/organ functions. This regulatory mechanism by fibronectin could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases. It is obvious that fibronectin matrix networks play crucial roles in many important biological events and in adult homeostasis. Therefore, the regulation of TGF-β bioavailability by fibronectin with retaining fibronectin matrix networks would be an essential element for long-term antifibrotic strategies in chronic fibrotic diseases to preserve tissue/ organ function and homeostasis.

Considering the adult tissue/organ remodeling following injury, important unresolved questions are (1) what is the trigger for fibrosis resolution (regression); and (2) how fibrosis resolution proceeds. Quiescent HSCs are adipocyte-like (vitamin A stock) cells expressing marker genes such as PPARγ, SREBP-1c, and leptin, whereas activated HSCs are proliferative myofibroblasts expressing myogenic marker α-SMA, c-myb, and MEF-2 [131]. CCl4-induced experimental liver injury models have suggested that elimination of activated HSCs by apoptosis [132] or senescence [133] is a key step in the onset of fibrosis regression [134]. Growing evidence demonstrates that activated HSCs are reverted to quiescent-like state both *in vitro* [135, 136] and *in vivo* [137, 138], and a very recent *in vitro* study using human primary HSCs reveals EGF, fibroblast growth factor 2, fatty acids, and retinol as potential factors in activated HSCs to reverse quiescent-like phenotypes [139]. Interestingly, reverted HSCs show more rapid reactivation into myofibroblasts in response to TGF-β than quiescent HSCs [137]. It is therefore likely that reverted HSCs may not fully revert to a quiescent state [134]. A recent elegant study demonstrates that a history of liver injury is transmitted to offspring via epigenetic modification of PPARγ and TGF-β genes in rats, and consequently, healing response to hepatic injury is suppressed in offspring of CCl4-injured group compared to injuryinexperienced group [140]. Nevertheless, the clarification of molecular mechanisms underly‐ ing excessive accumulation of collagenous ECM during the development of chronic fibrotic diseases could translate basic antifibrotic research into improved clinical therapeutic ap‐ proaches, which will have a significant benefit in public health impact. Thus, an establishment of novel models/systems, e.g., in which we enable to analyze global alterations of signaling cascades/metabolisms or epigenetics, would be crucial for challenging these complicated mechanisms in chronic fibrotic diseases.
