Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration

Luo, Hua; Sun, Cong; Zhu, Yu; Wang, Ying; Wang, Tao; Li, Sha; Cai, Wan Hui; Zheng, Jing; Zhou, Xuan; Cong, Wei; Li, Xiao Kun; Jin, Li

doi:10.1016/j.yexcr.2017.03.054

Cited by 20 publications

(26 citation statements)

References 36 publications

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“…The expression levels of these genes started to decline in the samples collected 3 h post-stimulation ( Figure 5 C). Hedgehog (Hh) signaling pathway is implicated in wound healing through the activation of cell proliferation and angiogenesis [ 39 , 40 , 41 ]. To investigate the potential activation of the Hh signaling pathway upon microcurrent stimulation in NIH3T3 cells, the expression levels of Smo , Ptch1 , Gli3 were examined by real-time PCR.…”

Section: Resultsmentioning

confidence: 99%

Microcurrent Stimulation Triggers MAPK Signaling and TGF-β1 Release in Fibroblast and Osteoblast-Like Cell Lines

Konstantinou

Zagoriti

Pyriochou

et al. 2020

Cells

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Wound healing constitutes an essential process for all organisms and involves a sequence of three phases. The disruption or elongation of any of these phases can lead to a chronic or non-healing wound. Electrical stimulation accelerates wound healing by mimicking the current that is generated in the skin after any injury. Here, we sought to identify the molecular mechanisms involved in the healing process following in vitro microcurrent stimulation—a type of electrotherapy. Our results concluded that microcurrents promote cell proliferation and migration in an ERK 1/2- or p38-dependent way. Furthermore, microcurrents induce the secretion of transforming growth factor-beta-1 (TGF-β1) in fibroblasts and osteoblast-like cells. Interestingly, transcriptomic analysis uncovered that microcurrents enhance the transcriptional activation of genes implicated in Hedgehog, TGF-β1 and MAPK signaling pathways. Overall, our results demonstrate that microcurrents may enhance wound closure through a combination of signal transductions, via MAPK’s phosphorylation, and the transcriptional activation of specific genes involved in the healing process. These mechanisms should be further examined in vivo, in order to verify the beneficial effects of microcurrents in wound or fracture healing.

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Section: Resultsmentioning

confidence: 99%

Microcurrent Stimulation Triggers MAPK Signaling and TGF-β1 Release in Fibroblast and Osteoblast-Like Cell Lines

Konstantinou

Zagoriti

Pyriochou

et al. 2020

Cells

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“…GSK3β-β-catenin signalling was reported to regulate cell migration in human fibroblasts via feedback regulation of basic fibroblast signalling (20). Another study demonstrated that key regulators of Hedgehog signalling, including Smo and Gli1, are controlled by β-catenin to modulate fibroblast cell migration (22). In addition, connections between Wnt and hedgehog signalling was reported (27).…”

Section: Discussionmentioning

confidence: 99%

“…In our transcriptome study using Wnt3a-stimulated cells, Wnt signalling activation was observed to alter the expression patterns of a large number of genes, including Hedgehog signalling genes (21). In addition, Hedgehog signalling genes have been demonstrated to regulate fibroblast repair and are controlled by β-catenin, a Wnt signalling regulator (22). However, the association between Wnt and Hedgehog signalling pathways remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Wnt3a‑regulated TCF4/β‑catenin complex directly activates the key Hedgehog signalling genes Smo and Gli1

Wang

Lin²,

Wang

et al. 2018

Exp Ther Med

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The Wnt and Hedgehog signalling pathways serve key roles in diverse developmental processes. However, the molecular associations between these two signalling pathways remains unclear. Previous transcriptome studies on human foreskin fibroblasts have indicated that Wnt signalling activation induces the expression of key Hedgehog signalling genes, including smoothened, frizzled class receptor () and GLI family zinc finger 1 (). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results revealed that Wnt3a treatment induced the expression of the key Hedgehog signalling genes, including , patched (), and. In addition, western blot analyses demonstrated that Wnt3a treatment resulted in the accumulation of cellular Smo and Gli proteins. Furthermore, promoter sequence analysis revealed that the putative β-catenin/T-cell factor (TCF)-4 complex binding motifs (//AAAG) were located within 1.5 kb of the and promoters. Results of the chromatin immunoprecipitation experiments and yeast-one hybrid assays revealed that TCF4 directly binds to the and promoters, with two binding sites for and a single binding site for. Further analysis showed that the β-catenin/TCF4 complex binds to the and promoters. To investigate the functions of TCF4 and β-catenin in transcriptional regulation of and and β- were transiently expressed in fibroblast cells. RT-qPCR results demonstrated that overexpression of and β- induced the expression of and. In addition, small interfering RNA-mediated suppression of β- resulted in the downregulation of and expression levels, even under Wnt3a treatment. Suppression of β- and expression inhibited cell proliferation. Taken together, the results of the present study suggested that the β-catenin/TCF4 complex directly activates and by binding to their promoters, which in turn controls cell proliferation in human fibroblasts.

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“…This result was confirmed using the lung transcriptome dataset from of an independent COPD cohort. Although significant, the minor differences in gene expression levels observed may be due to the sample collection technique, involving extraction of mRNA from both epithelium and subepithelial compartments with enriched HH players, such as fibroblasts [36].…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signalling as a potential endobronchial biomarker in COPD

et al. 2020

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Background: The hedgehog (HH) pathway has been associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies and recent studies suggest that HH signalling could be altered in COPD. We therefore used minimally invasive endobronchial procedures to assess activation of the HH pathway including the main transcription factor, Gli2, and the ligand, Sonic HH (Shh). Methods: Thirty non-COPD patients and 28 COPD patients were included. Bronchial brushings, bronchoalveolar lavage fluid (BALF) and bronchial biopsies were obtained from fiberoptic bronchoscopy. Characterization of cell populations and subcellular localization were evaluated by immunostaining. ELISA and RNAseq analysis were performed to identify Shh proteins in BAL and transcripts on lung tissues from non-COPD and COPD patients with validation in an external and independent cohort. Results: Compared to non-COPD patients, COPD patients exhibited a larger proportion of basal cells in bronchial brushings (26 ± 11% vs 13 ± 6%; p < 0.0001). Airway basal cells of COPD subjects presented less intense nuclear staining for Gli2 in bronchial brushings and biopsies (p < 0.05). Bronchial BALF from COPD patients contained lower Shh concentrations than non-COPD BALF (12.5 vs 40.9 pg/mL; p = 0.002); SHH transcripts were also reduced in COPD lungs in the validation cohort (p = 0.0001). Conclusion: This study demonstrates the feasibility of assessing HH pathway activation in respiratory samples collected by bronchoscopy and identifies impaired bronchial epithelial HH signalling in COPD.

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Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration

Cited by 20 publications

References 36 publications

Microcurrent Stimulation Triggers MAPK Signaling and TGF-β1 Release in Fibroblast and Osteoblast-Like Cell Lines

Microcurrent Stimulation Triggers MAPK Signaling and TGF-β1 Release in Fibroblast and Osteoblast-Like Cell Lines

Wnt3a‑regulated TCF4/β‑catenin complex directly activates the key Hedgehog signalling genes Smo and Gli1

Sonic hedgehog signalling as a potential endobronchial biomarker in COPD

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