Substrate Stiffness Influences the Time Dependence of CTGF Protein Expression in Müller Cells

Davis, Joshua; Foster, William

doi:10.14302/issn.2578-8590.ipj-17-1910

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Given the fact that, in our study, TGF-β1 secretion was unaltered and an increase in DCN secretion was observed, it was not surprising that no change in CTGF secretion was found in response to increasing stiffness. CTGF has also been reported to be downstream of YAP, and we reported there was more YAP retention in the cytoplasm potentially contributing to less upregulation in response to the stiffer environment (Davis and Foster, 2018;Shome et al, 2020). In addition, there was downregulation of CTGF gene expression in response to stiffer hydrogels confirming the findings that protein secretion was unaltered.…”

Section: Discussionsupporting

confidence: 82%

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Blokland

Nizamoglu²,

Habibie³

et al. 2022

Front. Pharmacol.

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In fibrosis remodelling of ECM leads to changes in composition and stiffness. Such changes can have a major impact on cell functions including proliferation, secretory profile and differentiation. Several studies have reported that fibrosis is characterised by increased senescence and accumulating evidence suggests that changes to the ECM including altered composition and increased stiffness may contribute to premature cellular senescence. This study investigated if increased stiffness could modulate markers of senescence and/or fibrosis in primary human lung fibroblasts. Using hydrogels representing stiffnesses that fall within healthy and fibrotic ranges, we cultured primary fibroblasts from non-diseased lung tissue on top of these hydrogels for up to 7 days before assessing senescence and fibrosis markers. Fibroblasts cultured on stiffer (±15 kPa) hydrogels showed higher Yes-associated protein-1 (YAP) nuclear translocation compared to soft hydrogels. When looking at senescence-associated proteins we also found higher secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) but no change in transforming growth factor-β1 (TGF-β1) or connective tissue growth factor (CTGF) expression and higher decorin protein deposition on stiffer matrices. With respect to genes associated with fibrosis, fibroblasts on stiffer hydrogels compared to soft had higher expression of smooth muscle alpha (α)-2 actin (ACTA2), collagen (COL) 1A1 and fibulin-1 (Fbln1) and higher Fbln1 protein deposition after 7 days. Our results show that exposure of lung fibroblasts to fibrotic stiffness activates genes and secreted factors that are part of fibrotic responses and part of the Senescence-associated secretory phenotype (SASP). This overlap may contribute to the creation of a feedback loop whereby fibroblasts create a perpetuating cycle reinforcing progression of a fibrotic response.

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Section: Discussionsupporting

confidence: 82%

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Blokland

Nizamoglu²,

Habibie³

et al. 2022

Front. Pharmacol.

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show abstract

“…Given the fact that, in our study, TGF-β1 secretion was unaltered and an increase in DCN secretion was observed, it was not surprising that no change in CTGF secretion was found in response to stiffness. CTGF has also been reported to be downstream of YAP, and we reported there was more YAP retention in the cytoplasm potentially contributing to less upregulation in response to the stiff environment (66,67). In addition, there was downregulation of CTGF gene expression in response to stiff hydrogels confirming the findings that protein secretion was unaltered.…”

Section: Discussionsupporting

confidence: 82%

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Blokland

Nizamoglu

Habibie

et al. 2022

Preprint

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In idiopathic pulmonary fibrosis (IPF) there is excessive ECM deposition, increased stiffness and ultimately destruction of lung parenchyma. IPF presents mainly in the elderly, implying that senescence, a hallmark of ageing, contributes to disease progression. Several studies have reported that IPF is characterised by increased senescence and accumulating evidence suggests that structural changes, such as increased stiffness may contribute to senescence. This study therefore investigated if increased tissue stiffness could modulate markers of senescence and/or fibrosis in primary lung fibroblasts. Using hydrogels representing healthy and fibrotic stiffnesses, we cultured primary fibroblasts from non-diseased lung tissue on top of these hydrogels for up to seven days before assessing senescence and fibrosis markers. Fibroblasts cultured on stiff (+/-15kPa) hydrogels showed higher Yes-associated protein-1 (YAP) nuclear translocation compared to soft hydrogels. When looking at senescence-associated proteins we also found higher secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) but no change in transforming growth factor-Beta1 (TGF-B1) or connective tissue growth factor (CTGF) expression and higher decorin protein deposition on stiff matrices. With respect to genes associated with fibrosis, fibroblasts on stiff hydrogels compared to soft had higher expression of smooth muscle alpha (α)-2 actin (ACTA2), collagen (COL) 1A1 and fibulin-1 (Fbln1) and higher Fbln1 protein deposition after seven days. Our results show that exposure of lung fibroblasts to fibrotic stiffness activates genes and secreted factors that are part of fibrotic responses and part of the senescence-associated secretory profile (SASP). This overlap may contribute to the creation of a feedback loop whereby fibroblasts create a perpetuating cycle reinforcing disease progression in IPF.

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“…Furthermore, changes in YAP/ TAZ localization and CTGF protein expression in Müller cells may contribute to the development of PVR/retinal gliosis during retinal detachment. 72 These findings reveal how the Hippo pathway and other signalling pathways interact to contribute to PVR development. Thus, targeting YAP/TAZ activity may be a potential therapy to slow the progression of PVR.…”

Section: Immunohistochemical Analysis Of Vegfr2 and Yap In Human Pvrmentioning

confidence: 87%

The Hippo signalling pathway and its impact on eye diseases

2024

J Cellular Molecular Medi

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The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies.

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Substrate Stiffness Influences the Time Dependence of CTGF Protein Expression in Müller Cells

Cited by 7 publications

References 25 publications

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

The Hippo signalling pathway and its impact on eye diseases

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