Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer.

Organ fibrosis is characterized by the accumulation of disorganized and stiff extracellular matrix (ECM) and represents the final stage of several life-threatening diseases. The progressive replacement of normal tissue by fibrotic ECM impedes organ functionality to the point of failure. Fibrosis affects millions of people worldwide with no effective cure for various reasons: (a) Due to the lack of clinical biomarkers and non-invasive detection methods fibrosis is often diagnosed too late, when organs are already destroyed beyond repair. (b) Fibrosis can be understood as dysregulated tissue repair that evolved robust programs to be able to respond to various injury scenarios. The redundant nature of these programs often evades linear therapeutic strategies. (c) Fibrosis perpetuates itself by establishing conditions that activate normal into fibrogenic cells which, in turn, create a pro-fibrotic environment. ECM takes center stage in the process of fibrosis as a defining feature and thus potential diagnostic biomarker. The ECM is also a main promoter of the disease process by providing lasting physicochemical pro-fibrotic cues to residing and recruiting cells. Effective anti-fibrotic therapies will need to take the lasting (mis-) instructive character of scar ECM into account. To restore organ functionality, it will be important to (re)turn fibrotic scar into functional ECM, for instance by dissolving fibrotic ECM and delivering cells with regenerative potential.