Concurrent YAP/TAZ and SMAD signaling mediate vocal fold fibrosis

Nakamura, Ryosuke; Hiwatashi, Nao; Bing, Renjie; Doyle, Carina; Branski, Ryan C.

doi:10.1038/s41598-021-92871-z

Cited by 24 publications

(28 citation statements)

References 61 publications

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“…An immortalized human VF fibroblast cell line, HVOX, 29 and macrophages derived from THP‐1 (ATCC, Manassas, Virginia, U.S.A.) were treated with 10 ng/ml TNF‐α, 100 ng/ml IFN‐γ, or 40 ng/ml IL4 ± various concentrations of GCs for 24 h.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid Dose Dependency on Gene Expression in Vocal Fold Fibroblasts and Macrophages

et al. 2022

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Objective Glucocorticoids (GCs) modulate multiple cellular activities including inflammatory and fibrotic responses. Outcomes of GC treatment for laryngeal disease vary, affording opportunity to optimize treatment. In the current study, three clinically employed GCs were evaluated to identify optimal in vitro concentrations at which GCs mediate favorable anti‐inflammatory and fibrotic effects in multiple cell types. We hypothesize a therapeutic window will emerge as a foundation for optimized therapeutic strategies for patients with laryngeal disease. Study Design In vitro. Methods Human vocal fold fibroblasts and human macrophages derived from THP‐1 monocytes were treated with 0.03–1000 nM dexamethasone, 0.3–10,000 nM methylprednisolone, and 0.3–10,000 nM triamcinolone in combination with interferon‐γ, tumor necrosis factor‐α, or interleukin‐4. Real‐time polymerase chain reaction was performed to analyze inflammatory (CXCL10, CXCl11, PTGS2, TNF, IL1B) and fibrotic (CCN2, LOX, TGM2) genes, and TSC22D3, a target gene of GC signaling. EC50 and IC50 to alter inflammatory and fibrotic gene expression was calculated. Results Interferon‐γ and tumor necrosis factor‐α increased inflammatory gene expression in both cell types; this response was reduced by GCs. Interleukin‐4 increased LOX and TGM2 expression in macrophages; this response was also reduced by GCs. GCs induced TSC22D3 and CCN2 expression independent of cytokine treatment. EC50 for each GC to upregulate CCN2 was higher than the IC50 to downregulate other genes. Conclusion Lower concentrations of GCs repressed inflammatory gene expression and only moderately induced genes involved in fibrosis. These data warrant consideration as a foundation for optimized clinical care paradigms to reduce inflammation and mitigate fibrosis. Level of Evidence NA Laryngoscope, 133:1169–1175, 2023

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Section: Methodsmentioning

confidence: 99%

Glucocorticoid Dose Dependency on Gene Expression in Vocal Fold Fibroblasts and Macrophages

et al. 2022

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“…As expected, the inhibition of the YAP signaling pathway by siRNA against YAP reversed the inhibitory effect of S1PR2 overexpression on the phosphorylation of YAP at Ser127 (Figure 6B). Previous investigations showed that the YAP nuclear localization was involved in the regulation of the canonical profibrotic signaling pathway TGF‐β 30 . We next investigated whether S1PR2 influenced TGF‐β signaling via the YAP pathway in HLSECs.…”

Section: Resultsmentioning

confidence: 99%

“…38 In consistence with previous studies, we detected that YAP dephosphorylation and nuclear localization were induced by S1pr2 signaling in liver sinusoidal endothelial cells. Furthermore, it has been shown that the YAP/TGF-β signaling was involved in the regulation of fibroblast proliferation migration and myofibroblasts differentiation, and therefore tightly controlled tissue fibrosis after injury, 30,39,40 suggesting that LSEC-S1pr2-YAP signaling might be involved in the modulation of HSC functions that determined the development of tissue fibrosis. Nakamura R et al reported that YAP/TAZ integrated diverse cell signaling events and interacted with signaling pathways related to tissue fibrosis, including the TGF-β/SMAD pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Nakamura R et al reported that YAP/TAZ integrated diverse cell signaling events and interacted with signaling pathways related to tissue fibrosis, including the TGF‐β/SMAD pathway 30 . Their investigation further showed that YAP functioned as an essential modulator of TGF‐β‐induced myofibroblast transformation 30 . Nakamura R et al identified that YAP/TAZ is located in close proximity to Smad2/3 and to regulate TGF‐β‐mediated fibrotic changes in conjunctival fibroblasts 30 .…”

Section: Discussionmentioning

confidence: 99%

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Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF‐β signaling pathway

et al. 2023

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The hepatic vascular niche plays an important role in the pathological process of liver fibrosis. Liver sinusoidal endothelial cells (LSECs) predominantly compose hepatic vascular niches. Endothelial cell (EC)-expressing sphingosine 1-phosphate receptor 2 (S1pr2) plays an essential role in the regulation of vascular functions.Nevertheless, it remains unknown whether liver LSEC-S1pr2 might modulate pathological liver fibrosis. In this study, liver fibrosis was induced by hepatotoxin carbon tetrachloride (CCl 4 ). The expression of S1pr2 is significantly downregulated in liver sinusoidal endothelial cells after CCl 4 treatment. The loss of S1pr2 in LSECs significantly alleviated liver fibrosis after chronic insult, whereas the overexpression of S1pr2 in LSECs accentuated liver fibrogenesis. In vivo experiments further revealed that the deficiency of S1pr2 in LSECs dampened hepatic stellate cell (HSC) activation, while overexpression of S1pr2 in LSECs enhanced HSC activation with more extracellular matrix component production. Mechanistically, LSEC-S1pr2 activates the YAP signaling pathway to potentiate the transactivation of TGF-β, which acts on HSCs in a paracrine manner, and thus aggravated liver fibrosis.Taken together, our results uncover a novel pathological mechanism of liver fibrosis in which LSEC-S1pr2 plays an important role in modulating the development of liver fibrosis, providing a future novel therapy target against liver fibrogenesis.

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“…Besides miRNAs, protein components in the pMSC-exos are also considered to play a key role in inhibiting the YAP signaling pathway, which needs to be investigated in the future. Moreover, it has been reported that TGFβ1 also activate YAP in fibroblasts (Nakamura et al, 2021); thus, the inhibitory effect of pMSC-exos on the YAP signaling pathway may also be related to their targeted regulation of TGFβ1.…”

Section: Pmsc-exos Prevent En1 Activationmentioning

confidence: 98%

Placental stem cells-derived exosomes stimulate cutaneous wound regeneration via engrailed-1 inhibition

Zhang

Shi

et al. 2022

Front. Bioeng. Biotechnol.

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Introduction: Skin wounds generally heal by scarring, a fibrotic process mediated by the Engrailed-1 (EN1) fibroblast lineage. Scar is detrimental to tissue structure and function, but perfect healing in clinical settings remains to be explored. Recent studies have shown that mesenchymal stem cell (MSC) transplantation can reduce scarringMethods: Here, we investigated the effects of placental MSCs (pMSCs) and exosomes derived from pMSCs (pMSC-exos) on wound healing using a full-thickness rat model.Results: The results showed that placental MSCs significantly accelerated the wound healing rate. Moreover, placental MSCs improved the quality of wound healing, including regenerating cutaneous appendages (hair follicles and sebaceous glands), decreasing collagen I and increasing collagen III, and improving collagen pattern (basket-wave-like) in the healed skin. placental MSCs treatment also increased the regeneration of blood vessels. Importantly, all these listed effects of placental MSCs were comparable to those of exosomes derived from pMSCs, but significantly stronger than those of adipose MSC-derived exosomes (aMSC-exos). Further studies showed that the effects of placental MSCs and exosomes derived from pMSCs on wound regeneration may be mainly achieved via the down-regulation of the Yes-associated protein signaling pathway, thus inhibiting the activation of EN1. Discussion: In summary, placental MSCs could effectively stimulate wound regeneration, and their effect could be achieved through their exosomes. This suggests that exosomes derived from pMSCs treatment could be used as a novel cell-free approach to induce wound regeneration in clinical settings.

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Concurrent YAP/TAZ and SMAD signaling mediate vocal fold fibrosis

Cited by 24 publications

References 61 publications

Glucocorticoid Dose Dependency on Gene Expression in Vocal Fold Fibroblasts and Macrophages

Glucocorticoid Dose Dependency on Gene Expression in Vocal Fold Fibroblasts and Macrophages

Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF‐β signaling pathway

Placental stem cells-derived exosomes stimulate cutaneous wound regeneration via engrailed-1 inhibition

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