Notch in fibrosis and as a target of anti-fibrotic therapy

Hu, Biao; Phan, Sem H.

doi:10.1016/j.phrs.2016.04.010

Cited by 112 publications

(84 citation statements)

References 128 publications

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“…Moreover, augmentation of Notch3 expression by lentiviral transfection inhibited fibroblast–myofibroblast transition both in TGF-β1-treated cardiac fibroblasts in vitro and in mice with MI, minimizing cardiac fibrosis (Zhang et al, 2016). As previously mentioned, Notch signaling can inhibit EMT (Zhou et al, 2015; Hu and Phan, 2016), which also contributes to cardiac fibrosis (von Gise and Pu, 2012). This point, however, remains controversial: indeed, in Notch transgenic mice undergoing MI and pressure overload, Notch induced epicardial cells to undergo EMT and generate a multipotent stromal cell population capable of differentiating into fibroblasts and producing reparative fibrosis (Russell et al, 2011).…”

Section: Notch Pathway In Cardiac Fibrosismentioning

confidence: 99%

“…Another morphogenetic effect of the Notch pathway with major repercussions on the adult diseased heart is the regulation of stromal cell differentiation and extracellular matrix (ECM) production (Hu and Phan, 2016). In the embryo, Notch signaling promotes EMT and generates mesenchymal cells: in turn, these cells differentiate into different stromal cell lineages, including the cardiac valves and coronary endothelium.…”

Section: Notch Pathway In the Developing And Diseased Heartmentioning

confidence: 99%

“…In the embryo, Notch signaling promotes EMT and generates mesenchymal cells: in turn, these cells differentiate into different stromal cell lineages, including the cardiac valves and coronary endothelium. Although in adult tissues EMT is suspected to play some role in the generation of new fibroblasts and myofibroblasts, the main pro-fibrotic cells, during the development of organ fibrosis (Hu and Phan, 2016), the existing evidence suggests that Notch signaling can rather exert anti-fibrotic effects on the diseased heart, for instance by counteracting the pro-fibrotic cytokine transforming growth factor (TGF)-β and reducing myofibroblast proliferation (Nemir et al, 2014). …”

Section: Notch Pathway In the Developing And Diseased Heartmentioning

confidence: 99%

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Notch Signaling in Ischemic Damage and Fibrosis: Evidence and Clues from the Heart

2017

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Notch signaling is a major intercellular coordination mechanism highly conserved throughout evolution. In vertebrates, Notch signaling is physiologically involved in embryo development, including mesenchymal cell commitment, formation of heart tissues and angiogenesis. In post-natal life, Notch signaling is maintained as a key mechanism of cell–cell communication and its dysregulations have been found in pathological conditions such as ischemic and fibrotic diseases. In the heart, Notch takes part in the protective response to ischemia, being involved in pre- and post-conditioning, reduction of reperfusion-induced oxidative stress and myocardial damage, and cardiomyogenesis. Conceivably, the cardioprotective effects of Notch may depend on neo-angiogenesis, thus blunting lethal myocardial ischemia, as well as on direct stimulation of cardiac cells to increase their resistance to injury. Another post-developmental adaptation of Notch signaling is fibrosis: being involved in the orientation of mesenchymal cell fate, Notch can modulate the differentiation of pro-fibrotic myofibroblasts, e.g., by reducing the effects of the profibrotic cytokine TGF-β. In conclusion, Notch can regulate the interactions between heart muscle and stromal cells and switch cardiac repair from a pro-fibrotic default pathway to a pro-cardiogenic one. These features make Notch signaling a suitable target for new cardiotropic therapies.

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Section: Notch Pathway In Cardiac Fibrosismentioning

confidence: 99%

Section: Notch Pathway In the Developing And Diseased Heartmentioning

confidence: 99%

Section: Notch Pathway In the Developing And Diseased Heartmentioning

confidence: 99%

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Notch Signaling in Ischemic Damage and Fibrosis: Evidence and Clues from the Heart

2017

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“…Given the increased ECM present in fibrotic tissues, it is not surprising that integrins figure predominantly in the pathology of fibrosis [97-99]. Adding to this, it has become apparent that Notch is also an important regulator of fibrosis in the lung, liver, kidney, and skin [100, 101]. For example, strong expression of Notch was observed in myofibroblasts, the pathological cells associated with the progression of fibrosis, in lung specimens from patients with idiopathic interstitial pneumonias and in bleomycin-induced pulmonary model of fibrosis [102].…”

Section: Crosstalk Between Notch and Integrinsmentioning

confidence: 99%

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

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The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

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“…The development of fibrosis presents a great challenge to researchers202122. The control of fibrosis remains elusive, although some progress has been made232425.…”

Section: Discussionmentioning

confidence: 99%

Involvement of eIF6 in external mechanical stretch–mediated murine dermal fibroblast function via TGF-β1 pathway

Qin

Tan

Daele

et al. 2016

Sci Rep

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External mechanical loading on a wound commonly increases fibrosis. Transforming growth factor-β1 (TGF-β1) has been implicated in fibrosis in various models, including the mechanical force model. However, the underlying mechanism is unclear. Our previous experiments suggested that eukaryotic initiation factor 6 (eIF6) acted as a regulator of TGF-β1 expression, and negatively impact on collagen synthesis. Our current results showed that external mechanical stretching significantly increased COL1A1, TGF-β1 and eIF6 expression as well as dermal fibroblasts proliferation, both in vitro and in vivo. eIF6 –deficient (eIF6+/−) cells exhibited significantly higher levels of COL1A1, and these levels increased further with external mechanical stretching, suggesting that mechanical stretching plays a synergistic role in promoting COL1A1 expression in eIF6+/− cells. Inhibition of TGFβR I/II by LY2109761 decreased COL1A1 protein expression in eIF6+/− dermal fibroblasts in a cell stretching model, and attenuated granulation tissue formation in partial thickness wounds of eIF6+/− mice. These data suggest that mechanical stretching has a synergistic role in the expression of COL1A1 in eIF6+/− cells, and is mediated by activation of TGFβRI/II. Taken together, our results indicate that eIF6 may be involved in external mechanical force-mediated murine dermal fibroblast function at least partly through the TGF-β1 pathway.

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Notch in fibrosis and as a target of anti-fibrotic therapy

Cited by 112 publications

References 128 publications

Notch Signaling in Ischemic Damage and Fibrosis: Evidence and Clues from the Heart

Notch Signaling in Ischemic Damage and Fibrosis: Evidence and Clues from the Heart

Notch: A multi-functional integrating system of microenvironmental signals

Involvement of eIF6 in external mechanical stretch–mediated murine dermal fibroblast function via TGF-β1 pathway

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