![]() Moreover, membrane-bound matrix metalloproteinase (MT1-MMP)-deficient mice that show a deficiency of membrane-type MMP-14, the metalloproteinase responsible for pericellular proteolysis of ECM, develop progressive fibrosis of the dermis and hair follicles. Indeed, numerous fibrotic-related human liver diseases, including biliary atresia, primary biliary cirrhosis, and primary sclerosing cholangitis, are associated with TIMP-1 and TIMP-2 overexpression. These processes are disrupted in fibrotic organs and directed toward ECM accumulation, which is partially evoked by an increased expression of tissue inhibitors of matrix metalloproteinases (TIMPs) versus a decrease in matrix metalloproteinases (MMPs). In healthy tissues, there is a balance between the synthesis and degradation of collagen and other ECM components. ![]() This aberration leads to excessive deposition of ECM components, which impairs organ structure and function. The development of fibrotic diseases is associated with abnormal accumulation of myofibroblasts. Altogether, these factors affect myofibroblast differentiation and stimulate excessive deposition of connective tissue components. Despite showing different clinical features, the majority of fibrotic diseases share common pathological processes characterized by persistent inflammation leading to the production of growth factors, cytokines, and proteolytic enzymes. Most fibrotic diseases have a relatively well-described etiology, including genetic predisposition, lifestyle, or systemic disorders ( Figure 1). The fibrotic process affects nearly all solid tissues and organs, including the heart, kidney, lung, liver, and skin, and in the majority of cases, this condition results from an ongoing disease (e.g., asthma, hypertension, diabetes, myocardial infarction (MI)) that commonly triggers these tissues. We also discuss the contemporary status, challenges, and future perspectives of stem cell transplantation for therapeutic options in fibrotic diseases as well as we present recent patents for stem cell-based therapies in organ fibrosis.įibrosis is the excessive accumulation of extracellular matrix (ECM), which leads to impairment of organ function and is consequently associated with high morbidity and mortality. Although the results of the studies seem to be encouraging, there are many aspects of cell-based therapy, including the cell source, dose, administration route and frequency, timing of delivery, and long-term safety, that remain open areas for future investigation. In this review, we summarize in vitro studies, preclinical studies performed on animal models of human fibrotic diseases, and recent clinical trials on the efficacy of allogeneic and autologous stem cell applications in severe types of fibrosis that develop in lungs, liver, heart, kidney, uterus, and skin. Since stem cells, especially mesenchymal stem cells (MSCs), show remarkable self-renewal, differentiation, and immunomodulatory capacity, they have been intensively tested in preclinical studies and clinical trials as a potential tool to slow down the progression of fibrosis and improve the quality of life of patients with fibrotic disorders. Although intensive research on the development of new strategies for fibrosis treatment has been carried out, therapeutic approaches remain limited. It has been estimated that severe fibrotic disorders are responsible for up to one-third of deaths worldwide. Thus, fibrosis leads to severe pathological conditions that disrupt organ architecture and cause loss of function. Fibrosis develops in response to a trigger or injury and can occur in nearly all organs of the body. Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components that result from the disruption of regulatory processes responsible for ECM synthesis, deposition, and remodeling.
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