Organ fibrosis is an integral part of the pathophysiological mechanism underlying organ failure and disease progression in a multitude of pathologies including Crohn's disease, nonalcoholic steatohepatitis and chronic kidney disease. Over the last decades, several signaling pathways involved in the fibrotic response have been identified, including the archetypal transforming growth factor beta (TGF-ß) and platelet-derived growth factor (PDGF) pathways as well as the Wnt, Hedgehog and the MAPK/ERK pathways. And a cornucopia of information on the minute details of receptor activation, the intracellular signaling cascade and associated proteins are emerging. Greatly increasing our ability to modulate and interfere with the fibrotic process. However, many of the triggers inducing fibrogenesis remain to be elucidated. Matrix-producing cells, e.g. myofibroblasts, are key players in organ fibrosis, and a lot of progress has been made in unraveling the origin of these cells, via lineage-tracing studies, during the fibrotic response in different organs, including kidney, liver and lung. These studies indicate that the process of epithelial-to-mesenchymal transition (EMT) hardly contributes to the development of myofibroblasts associated with fibrogenesis. Yet, the loss of epithelial cell characteristics by EMT – recently dubbed Epithelial Phenotypic Changes (EPC) - likely plays a key role in the pathological process of fibrosis.
In this Research Topic, we wish to provide a timely overview of disease- and organ-specific triggers associated with the induction and perpetuation of fibrogenesis. Moreover, we would like to provide a summary of the important signaling pathways in organ fibrosis, thereby providing new clues for potential anti-fibrotic targets. Also, we wish to summarize the current understanding of EPC in the fibrotic process and further define this pathophysiological mechanism. Lastly, submission of original experimental work on organ fibrosis is greatly welcomed.
Organ fibrosis is an integral part of the pathophysiological mechanism underlying organ failure and disease progression in a multitude of pathologies including Crohn's disease, nonalcoholic steatohepatitis and chronic kidney disease. Over the last decades, several signaling pathways involved in the fibrotic response have been identified, including the archetypal transforming growth factor beta (TGF-ß) and platelet-derived growth factor (PDGF) pathways as well as the Wnt, Hedgehog and the MAPK/ERK pathways. And a cornucopia of information on the minute details of receptor activation, the intracellular signaling cascade and associated proteins are emerging. Greatly increasing our ability to modulate and interfere with the fibrotic process. However, many of the triggers inducing fibrogenesis remain to be elucidated. Matrix-producing cells, e.g. myofibroblasts, are key players in organ fibrosis, and a lot of progress has been made in unraveling the origin of these cells, via lineage-tracing studies, during the fibrotic response in different organs, including kidney, liver and lung. These studies indicate that the process of epithelial-to-mesenchymal transition (EMT) hardly contributes to the development of myofibroblasts associated with fibrogenesis. Yet, the loss of epithelial cell characteristics by EMT – recently dubbed Epithelial Phenotypic Changes (EPC) - likely plays a key role in the pathological process of fibrosis.
In this Research Topic, we wish to provide a timely overview of disease- and organ-specific triggers associated with the induction and perpetuation of fibrogenesis. Moreover, we would like to provide a summary of the important signaling pathways in organ fibrosis, thereby providing new clues for potential anti-fibrotic targets. Also, we wish to summarize the current understanding of EPC in the fibrotic process and further define this pathophysiological mechanism. Lastly, submission of original experimental work on organ fibrosis is greatly welcomed.
![Active canonical WNT signaling in fibrosis. Simplified scheme showing the activated canonical WNT cascade and translocation of β-catenin. (A) WNT ligands bind to a frizzled receptor and form a complex with the co-receptor Lipoprotein-related-receptor protein (LRP). (B) The ubiquitination activity of the destruction complex [comprised of disheveled (DVL) Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3 (GSK3), and casein kinase 1(CK1)] is inhibited causing β-catenin to accumulate in the cytoplasm. (C) As later event, clusters of receptor complexes are internalized into endosomes, which triggers the sequestering of the destruction complex, and subsequent inhibition of GSK3. (D) GSK3 is then transported to multivesicular bodies where it cannot interact with cytoplasmic β-catenin, and thus protects β-catenin from proteasomal degradation. (E) Newly synthesized β-catenin translocates to the nucleus to interact with LEF/TCF transcription factors and other co-factors, such as p300 and CBP. (F) Termination of the WNT/β-catenin signaling cycle may occur through phosphorylation of β-catenin by protein kinase C (PKC)δ and subsequent ubiquitination by tripartite motif (TRIM)33. These steps target β-catenin for proteasomal degradation in the nucleus. (G) Another possible route for the termination of β-catenin activation is the cytoplasmic sequestering by 14-3-3ζ and Chibby (Cby).](https://www.frontiersin.org/_rtmag/_next/image?url=https%3A%2F%2Fwww.frontiersin.org%2Ffiles%2FArticles%2F153344%2Ffmed-02-00059-HTML%2Fimage_m%2Ffmed-02-00059-g002.jpg&w=3840&q=75)
