New Insights into the Mechanism of Notch Signalling in Fibrosis

Laboratoire d'immunologie, EA 1833, Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), France.
The Open Rheumatology Journal 06/2012; 6(1):96-102. DOI: 10.2174/1874312901206010096
Source: PubMed


The Notch pathway is an evolutionary conserved signalling mechanism that regulates cellular fate and development in various types of cells. The full spectrum of Notch effects has been well studied over the last decade in the fields of development and embryogenesis. But only recently several studies emphasized the involvement of the Notch signalling pathway in fibrosis. This review summarizes the structure and activation of the Notch family members, and focuses on recent findings regarding the role of Notch in organ fibrogenesis, in humans and in animal models.

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    • "Morphea is considered to be a result of the inflammatory cascade following vascular injury13. Hypoxia, reactive oxygen species, and TGF-β1 are suggested to be profibrotic factors in various fibroproliferative skin diseases such as morpheas and keloids5,21,22. The Notch signaling molecules in dermal fibroblasts are stimulated by hypoxia9,10, reactive oxygen species, or elevated levels of Ha-Ras and Ki-Ras23. "
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    ABSTRACT: BackgroundThe effects of the Notch signaling pathway in fibroproliferative skin diseases have not been fully elucidated.ObjectiveThe aim of this study was to investigate the expression of activated Notch signaling molecules in various skin fibroproliferative diseases.MethodsImmunohistochemical analysis of Notch intracellular domain (NICD) expression in keloid, hypertrophic scar, morphea, dermatofibroma, and normal control skin specimens was performed, and the clinical characteristics of patients with various skin fibroproliferative diseases were analyzed.ResultsNICD was highly expressed in fibroblasts of keloids and moderately to highly expressed in hypertrophic scars and dermatofibromas, whereas low or no expression was detected in the fibroblasts of normal skin specimens and morpheas. NICD was constitutively expressed in keratinocytes, endothelial cells, and immune cells in normal skin specimens.ConclusionNICD was significantly expressed in human fibroproliferative skin disorders, especially keloids, suggesting that an activated Notch signaling pathway is involved in the pathogenesis of skin fibrosis.
    Annals of Dermatology 06/2014; 26(3):332-7. DOI:10.5021/ad.2014.26.3.332 · 1.39 Impact Factor
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    • "Myofibroblasts are rarely found in healthy human physiology; they become vastly up-regulated after injury and play a critical role in the wound healing response (Gabbiani, 2003; Midwood et al., 2004). Myofibroblasts can originate from a variety of precursor cells, as shown in Figure 2. Major developmental signaling factors such as the Wnt (Liu et al., 2012), Notch (Kavian et al., 2012), and Sonic hedgehog ligands (Stewart et al., 2003; Ding et al., 2012) have well-described roles in myofibroblast differentiation from precursor cells. Myofibroblasts are well characterized to differentiate from resident fibroblasts in vivo and in vitro in response to profibrotic cytokine stimulation. "
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    ABSTRACT: Fibroblasts are the most common cell type of the connective tissues found throughout the body and the principal source of the extensive extracellular matrix (ECM) characteristic of these tissues. They are also the central mediators of the pathological fibrotic accumulation of ECM and the cellular proliferation and differentiation that occurs in response to prolonged tissue injury and chronic inflammation. The transformation of the fibroblast cell lineage involves classical developmental signaling programs and includes a surprisingly diverse range of precursor cell types-most notably, myofibroblasts that are the apex of the fibrotic phenotype. Myofibroblasts display exaggerated ECM production; constitutively secrete and are hypersensitive to chemical signals such as cytokines, chemokines, and growth factors; and are endowed with a contractile apparatus allowing them to manipulate the ECM fibers physically to close open wounds. In addition to ECM production, fibroblasts have multiple concomitant biological roles, such as in wound healing, inflammation, and angiogenesis, which are each interwoven with the process of fibrosis. We now recognize many common fibroblast-related features across various physiological and pathological protracted processes. Indeed, a new appreciation has emerged for the role of non-cancerous fibroblast interactions with tumors in cancer progression. Although the predominant current clinical treatments of fibrosis involve non-specific immunosuppressive and anti-proliferative drugs, a variety of potential therapies under investigation specifically target fibroblast biology.
    Frontiers in Pharmacology 05/2014; 5:123. DOI:10.3389/fphar.2014.00123 · 3.80 Impact Factor
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    ABSTRACT: Purpose of review: Interest in the myofibroblast as a key player in propagation of chronic progressive fibrosis continues to elicit many publications, with focus on its cellular origins and the mechanisms underpinning their differentiation and/or transition. The objective of the review is to highlight this recent progress. Recent findings: The epithelial origin of the myofibroblast in fibrosis has been challenged by recent studies, with the pericyte suggested as a possible precursor instead. Additional signaling pathways, including Notch, Wnt, and hedgehog, are implicated in myofibroblast differentiation. The importance of NADPH oxidase 4 was highlighted recently to suggest a potential link between cellular/oxidative stress and the genesis of the myofibroblast. Recent observations on the importance of lysophosphatidic acid in fibrosis suggest that this may be due, in part, to its ability to regulate myofibroblast differentiation. Finally, there is increasing evidence for the role of epigenetic mechanisms in regulating myofibroblast differentiation, including DNA methylation and miRNA regulation of gene expression. Summary: These recent discoveries open up a whole new array of potential targets for novel antifibrotic therapies. This is of special importance given the current bleak outlook for chronic progressive fibrotic diseases, such as scleroderma, due to lack of effective therapies.
    Current opinion in rheumatology 10/2012; 25(1). DOI:10.1097/BOR.0b013e32835b1352 · 4.89 Impact Factor
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