ReviewTherapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer
Introduction
Fibrosis comprises a group of heterogeneous connective tissue disorders and is an end-stage condition of numerous fatal diseases. Fibrosis can develop in all organs and affects millions of people worldwide [1]. Examples of fibrotic lesions are the thick, raised scars resulting from deep skin burns [2], Dupuytren disease [3], encapsulation of implants as part of the foreign body reaction [4], life-threatening fibrosis of lungs [5,6], kidneys [7], heart [8], liver [9] and multiple organ-fibrosis in systemic sclerosis [10]. By stimulating tissue repair programs, tumors create a fibrotic environment in the surrounding stroma that promotes tumor growth and metastasis [11,12]. The main effector cells in all fibrotic diseases are myofibroblasts, which are activated by injury signals to secrete and contract extracellular matrix (ECM) into mechanically stabilizing scar tissue [7,9,[13], [14], [15]] (Fig. 1). This critical repair function is perverted in fibrosis when myofibroblast deregulation results in the replacement of functional tissue architecture with disorganized fibrillar ECM.
Accumulation of stiff and disorganized ECM progressively impedes tissue function and can ultimately cause organ failure. In the heart, fibrosis of the ventricular wall impedes contraction and systemic perfusion, fibrosis of the myocardium reduces ventricular filling and causes diastolic heart failure, and fibrosis of the valves disturbs proper blood flow [16,17]. In fibrotic lung, accumulation of ECM in the alveolar space affects gas exchange and lung expansion during breathing [[18], [19], [20]]. In the liver, replacement of functional cells with fibrotic ECM causes hepatocellular dysfunction, hepatic insufficiency and portal hypertension [21]. In the kidney, accumulation of collagenous ECM in the interstitial space and glomeruli reduces kidney volume, compromises perfusion and destroys the delicate nephron structure required for filtering [7]. Dense ECM also reduces or abolishes the function of implants such as electrodes and insulin pumps [4]. In all fibrotic conditions, ECM interferes with effective delivery of therapeutics by presenting a mechanical obstacle; a feature that is particularly problematic for tumor treatments [[22], [23], [24]].
In this review we focus on the relevance of ECM accumulation not only as a result of fibrogenesis but also as central factor in promoting disease progression. We propose that the ECM can become a powerful pro-fibrotic stimulus and that the search for a cure for fibrosis should consider fibrotic ECM components as therapeutic targets. To restore organ functionality, it will be important not only to halt fibrosis progression but to revert scar into healthy/functional ECM. We will discuss the potential of using mesenchymal cell therapies to stimulate regeneration rather than repair.
Section snippets
Why is there still no cure for fibrosis?
In 2017, more than 2600 clinical studies were listed on clinicaltrials.gov with keyword “fibrosis”, of which over 800 were active. Despite these substantial efforts, there is still no effective cure for fibrosis - organ replacement (e.g., lung or skin transplants) is often the only available option for severely affected patients. The difficulty to cure fibrosis has various reasons, some of which may be overcome by taking the fibrotic ECM into consideration (Table 1).
Properties and components of the fibrotic ECM
Fibrotic ECM of different organs shares common molecular and physical characteristics that differ from normal tissue, such as accumulation of specific collagens, fibronectins and proteoglycans, and high stiffness [6,16,20,51]. We have previously reviewed molecular components of fibrotic ECM [89] and here provide a brief update. Characteristic ECM components of fibrotic tissues and their functions [[239], [240], [241], [242], [243], [244], [245], [246], [247], [248], [249], [250], [251], [252],
Resolving fibrosis by dissolving ECM?
Treatments that halt fibrosis will unlikely be sufficient to fully restore organ function. To regain function, diseased and mis-instructive ECM needs to be removed and/or replaced with “healthy” ECM in a controlled manner [162,163] (Table 4). Viral hepatitis-infected liver is one of the few examples where even advanced fibrosis in humans can spontaneously resolve after removing the insult and ECM degradation is a key event in this process [164,165].
Supporting tissue regeneration with mesenchymal progenitor cells – benefits and risks
The tissue repair programs which promote fibrosis aim at quickly restoring lost tissue integrity at the expense of tissue functionality. Myofibroblasts repair but do not truly regenerate. Organisms with high regenerative potential have attenuated or absent fibrotic healing, including certain mammals such as the spiny mouse [187] and the developing human embryo [188,189]. To restore tissue homeostasis in adult organs after/during resolution of fibrosis, transplanting mesenchymal stromal/stem
Conclusions
Transformation of functional tissue into dense and obstructive ECM is a defining feature of fibrosis. Out of the good intention to contain damages and preserve tissue integrity after injury, beneficial repair programs turn into detrimental pathology. The same redundant mechanisms ensuring that tissue repair is sufficiently flexible to manage a vast variety of injuries often prevent successful therapy. New therapeutic strategies will need to build on our enhanced understanding how to manage the
Disclosures
The authors have approved the final version of this manuscript and have no conflicts of interest to declare.
Funding
The research of BH is supported by the Canadian Institutes of Health Research (CIHR), Foundation Grant #375597. MW is supported by post-doctoral fellowships from the CIHR and the Netherlands Organization for Scientific Research (NWO) through the Rubicon research programme.
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