NR4A1 is an endogenous inhibitor of vocal fold fibrosis

Hiwatashi, Nao; Bing, Renjie; Kraja, Iv; Branski, Ryan C.

doi:10.1002/lary.26678

Cited by 16 publications

(27 citation statements)

References 21 publications

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“…These assays are thought to reflect the physiological condition during wound healing and the fibrotic properties of stimulated cells. These data further confirm the antifibrotic features described in the gene analyses, and are compatible with our previous reports regarding accelerated contraction with siRNA for NR4A1 …”

Section: Discussionsupporting

confidence: 93%

“…Conversely, SMAD2 , SMAD3 , and SMAD7 expression did not change in response to Csn‐B. Our group previously reported siRNA for NR4A1 enhanced profibrotic features of TGF‐β1–stimulated cells with no significant changes in SMAD2 or SMAD3 expression . We observed the tendency toward upregulation of endogenous TGF‐β1 induced by Csn‐B.…”

Section: Discussionsupporting

confidence: 45%

“…Our group previously reported siRNA for NR4A1 enhanced profibrotic features of TGF-β1-stimulated cells with no significant changes in SMAD2 or SMAD3 expression. 14 We observed the tendency toward upregulation of endogenous TGF-β1 induced by Csn-B. Interestingly, no previous data describe a relationship between endogenous TGF-β1 and Csn-B, but presumably, this result could be derived from feedback of cellular antifibrotic signaling induced by Csn-B treatment.…”

Section: Discussionmentioning

confidence: 48%

“…In addition, cytosporone‐B (Csn‐B), a fungal metabolite, was identified as an agonist binding to the ligand‐binding domain of NR4A1 . Our group recently described enhanced fibrotic features in human vocal fold fibroblasts with NR4A1 knockdown; specifically, upregulation of extracellular matrix associated with tissue fibrosis, increased myofibroblast differentiation, and collagen gel contraction . Conversely, we hypothesized that Csn‐B would enhance the antifibrotic features of NR4A1 under TGF‐β1‐stimulation in human VFFs.…”

Section: Introductionmentioning

confidence: 98%

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The effects of cytosporone‐B, a novel antifibrotic agent, on vocal fold fibroblasts

et al. 2018

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Objectives/Hypothesis Our laboratory recently described NR4A1 as an endogenous inhibitor of TGF-β-induced vocal fold (VF) fibrosis. Our prior report described the temporal expression of NR4A1 during VF healing in vivo and the effects of NR4A1 knockdown on fibroplastic cell activities in vitro. Based on these findings, we hypothesized that Cytosporone-B (Csn-B), a NR4A1 agonist, may hold significant therapeutic potential. Study Design In vitro. Methods Human VF fibroblasts were exposed to TGF-β1+/-Csn-B. Expression of genes related to fibrosis were quantified. In addition, contraction was assayed as a surrogate for the fibrotic phenotype in our cell line. Results TGF-B1 stimulated COL1A1 and ACTA2, as expected. Csn-B significantly downregulated TGF-β1-mediated upregulation of these genes (p=0.009, p=0.03, respectively). Csn-B had no effect on genes related to TGF-β/Smad signaling. Csn-B also decreased the TGF-β1-mediated contractile phenotype in our cells (p=0.004). Conclusions NR4A1 is an endogenous inhibitor of fibrosis in the vocal folds and Csn-B, as an NR4A1 agonist, may evolve as an ideal, therapeutic candidate for this challenging condition. Level of Evidence N/A

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 98%

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The effects of cytosporone‐B, a novel antifibrotic agent, on vocal fold fibroblasts

et al. 2018

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“…Nuclei were counterstained with DAPI. Digital images were captured, and both the total cell count and ACTA2 positive cells were counted in 10 randomly chosen, 3.0 mm 2 fields for each condition under 10 × magnification …”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of the glucocorticoid receptor alters SMAD signaling in vocal fold fibroblasts

Mukudai¹,

Hiwatashi²,

Bing³

et al. 2018

The Laryngoscope

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Objectives/Hypothesis Direct glucocorticoid (GC) injection for vocal fold (VF) scarring has evolved as a therapeutic strategy, but the mechanisms underlying the antifibrotic effects remain unclear. GCs act via the glucocorticoid receptor (GR), which is phosphorylated at multiple serine residues in a hormone‐dependent manner to affect bioactivity. We hypothesize that GCs regulate SMAD signaling via GR phosphorylation in vocal fold fibroblasts (VFFs). Study Design In vitro. Methods Human VFFs were treated with dexamethasone (DM; 10−5–10−7M) ± transforming growth factor (TGF)‐β1 (10 ng/mL). RU486 (10−6M) was employed to isolate the regulatory effects of GR. Total GR, Ser211, and Ser203 phosphorylation was examined via sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and immunocytochemistry. Quantitative polymerase chain reaction was employed to determine GR‐mediated effects of DM on genes related to fibrosis. Results Total GR and Ser211 phosphorylation was observed predominantly in the nucleus 1 hour after DM administration. DM decreased total GR expression, but Ser203 and Ser211 phosphorylation increased. RU486 limited the effects of DM. SMAD3 and SMAD7 mRNA expression significantly decreased 4 hours after DM administration (P < 0.05); this response was negated by RU486. COL1A1 remained unchanged, and ACTA2 significantly increased following 24 hours of DM treatment (P < 0.05). Conclusion DM regulated TGF‐β1 signaling via altered SMAD3 and SMAD7 expression. This response was associated with altered GR phosphorylation. These findings provide insight into the mechanisms of steroidal effects on vocal fold repair; ultimately, we seek to enhance therapeutic strategies for these challenging patients. Level of Evidence NA Laryngoscope, 129:E187–E193, 2019

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Systemic Transplantation of Eyelid Adipose‐Derived Stem Cells for Antifibrotic Treatment

Fang

Chen

Teng

et al. 2020

Advanced Therapeutics

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Fibrosis is a result of the pathological wound‐healing response initiated by immune cells and leads to permanent scarring, such as corneal scarring, which impairs the vision of millions of people worldwide. However, there is currently no available treatment strategy that specifically targets the pathogenesis of fibrosis and can be translated in a safe and versatile way. Herein, it is illustrated that systemic transplantation of easily accessible human eyelid adipose‐derived stem cells (heADSCs) can successfully and safely exert antifibrotic effects in both corneal and skin scarring cases. Intravenous injection of heADSCs alleviates scar formation after rat corneal lamellar injury with accelerated epithelization, increases tumor necrosis factor‐stimulated gene‐6 (TSG‐6) in the epithelium, and decreases inflammatory factors. Cell tracing shows the presence of detectable signals until the 7th day, while no pulmonary embolism or other discomfort occurs. heADSCs effectively reduce corneal scarring by ameliorating stromal inflammation by increasing endogenous tissue‐protective TSG‐6 in the epithelium and macrophage phenotype switching, which is more effective with systemic transplantation than subconjunctival transplantation. Systemic transplantation of heADSCs shows safe antifibrotic effects in both corneal and skin scarring cases and this result identifies systemic transplantation with autologous adipose‐derived stem cells as a generally versatile and safe therapy for antifibrotic treatment.

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NR4A1 is an endogenous inhibitor of vocal fold fibrosis

Cited by 16 publications

References 21 publications

The effects of cytosporone‐B, a novel antifibrotic agent, on vocal fold fibroblasts

The effects of cytosporone‐B, a novel antifibrotic agent, on vocal fold fibroblasts

Phosphorylation of the glucocorticoid receptor alters SMAD signaling in vocal fold fibroblasts

Systemic Transplantation of Eyelid Adipose‐Derived Stem Cells for Antifibrotic Treatment

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