Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation

Zhang, Tao; Wang, Xiaofeng; Wang, Zheng‐Cai; Lou, Dong; Fang, Qing‐Qing; Hu, Yawen; Zhao, Wan‐Yi; Zhang, Liyun; Wu, Lie; Tan, Wei‐Qiang

doi:10.1016/j.biopha.2020.110287

Cited by 208 publications

(179 citation statements)

References 133 publications

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“…Additionally, further in vivo and in vitro experimental exploration and validation are required. Moreover, transcriptome analysis for keloid, using microarray or not, has identified differentially expressed micro-RNAs [ 53 ] during keloid formation and long noncoding RNAs (lncRNAs) [ 54 ] between earlobe keloid and normal tissue. DEGs in fibroblast and keratinocytes between keloid and normal were also identified [ 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of Key Genes and Pathways Related to Keloids

Liu

et al. 2021

BioMed Research International

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Background. The pathophysiology of keloids is complex, and the treatment for keloids is still an unmet medical need. Our study is aimed at identifying the hub genes among the differentially expressed genes (DEGs) between normal skin tissue and keloids and key pathways in the development of keloids. Materials and Methods. We downloaded the GSE92566 and GSE90051 microarray data, which contain normal skin tissue and keloid gene expression data. GSE92566 was treated as a discovery dataset for summarizing the significantly DEGs, and GSE90051 served as a validation dataset. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome enrichment analysis, gene set enrichment analysis, and gene set variation analysis were performed for the key functions and pathways enriched in DEGs. Moreover, we also validated the hub genes identified from the protein-protein interaction network and predicted miRNA-hub gene interactions. Results. 117 downregulated DEGs and 204 upregulated DEGs in GSE92566 were identified. Extracellular and collagen-related pathways were prominent in upregulated DEGs, while the keratinization-related pathway was associated with downregulated DEGs. The hub genes included COL5A1, COL5A2, and SERPINH1, which were also validated in GSE90051. Conclusion. This study identified several hub genes and provided insights for the underlying pathways and miRNA-hub gene interactions for keloid development through bioinformatic analysis of two microarray datasets. Additionally, our results would support the development of future therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of Key Genes and Pathways Related to Keloids

Liu

et al. 2021

BioMed Research International

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“…Indeed, aberrant TGF-β signaling has been recognized in a wide spectrum of fibrotic diseases, not limited to systemic sclerosis [107], keloid [108], pulmonary fibrosis [109], hepatic fibrosis [110], renal fibrosis [111], cardiac fibrosis [112], myopathies [113], and salivary gland fibrosis [114]. Salivary gland fibrosis can be seen in chronic inflammation, aging, infections, ductal obstruction, physical trauma, irradiation, and autoimmune disease [10,11,115].…”

Section: Tgf-β Signaling In Salivary Gland Fibrosismentioning

confidence: 99%

TGF-β Pathway in Salivary Gland Fibrosis

Zhang

Yun

Han

et al. 2020

IJMS

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Fibrosis is presented in various physiologic and pathologic conditions of the salivary gland. Transforming growth factor beta (TGF-β) pathway has a pivotal role in the pathogenesis of fibrosis in several organs, including the salivary glands. Among the TGF-β superfamily members, TGF-β1 and 2 are pro-fibrotic ligands, whereas TGF-β3 and some bone morphogenetic proteins (BMPs) are anti-fibrotic ligands. TGF-β1 is thought to be associated with the pro-fibrotic pathogenesis of sialadenitis, post-radiation salivary gland dysfunction, and Sjögren’s syndrome. Potential therapeutic strategies that target multiple levels in the TGF-β pathway are under preclinical and clinical research for fibrosis. Despite the anti-fibrotic effect of BMPs, their in vivo delivery poses a challenge in terms of adequate clinical efficacy. In this article, we will review the relevance of TGF-β signaling in salivary gland fibrosis and advances of potential therapeutic options in the field.

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“…8k). It is worth noting that excessive activation of TGF-β/Smad signalling pathways and myofibroblasts is involved in pathological scar formation [38,39]. However, it is more likely that their activation is a physiological process in wound healing, considering that this process has been widely reported previously [40,41].…”

Section: Discussionmentioning

confidence: 95%

Human foreskin-derived dermal stem/progenitor cell-conditioned medium combined with hyaluronic acid promotes extracellular matrix regeneration in diabetic wounds

Wang

et al. 2021

Stem Cell Res Ther

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Background Diabetic wounds remain a challenging clinical problem, which requires further treatment development. Published data showed that dermis-derived stem/progenitor cells (DSPCs) display superior wound healing in vitro. The beneficial effects of DSPCs are mediated through paracrine secretion, which can be obtained from conditioned medium (CM). Hyaluronic acid (HA) is especially suitable for skin regeneration and delivering bioactive molecules in CM. This study investigated the effect of human foreskin-derived dermal stem/progenitor cell (hFDSPC)-CM combined with HA on a diabetic mouse model and relevant mechanism in vitro. Methods hFDSPCs and human adipose-derived stem cells (hADSCs) were identified, and the respective CM was prepared. PBS, HA, hFDSPC-CM combined with HA, or hADSC-CM combined with HA was topically applied to mice. HE, CD31, CD68, CD86, and CD206 staining was performed to evaluate gross wound condition, angiogenesis, and inflammation, respectively. Masson and Picrosirius red staining was performed to evaluate collagen deposition and maturation. The effects of hFDSPC-CM and hADSC-CM on human keratinocyte cells (HaCaT) and fibroblasts were evaluated in vitro using CCK-8 and EdU assays to determine cell viability and proliferation, respectively. The scratch assay was performed to evaluate cell migration. Tube formation assay was performed on human umbilical vein endothelial cells (HUVECs) to confirm angiogenesis. Extracellular matrix (ECM) metabolic balance-related genes and proteins, such as collagen I (COL 1), collagen III (COL 3), fibronectin (FN), α-SMA, matrix metalloproteinases 1 (MMP-1), matrix metalloproteinases 3 (MMP-3), and transforming growth factor-beta 1 (TGF-β1), were analysed. Results hFDSPC-CM combined with HA showed superior wound closure rate over hADSC-CM. Histologically, the hFDSPC-CM combined with HA group showed significantly improved re-epithelialisation, angiogenesis, anti-inflammation, collagen regeneration, and maturation compared to hADSC-CM combined with HA group. In vitro assays revealed that hFDSPC-CM displayed significant advantages on cell proliferation, migration, and ECM regeneration through a TGF-β/Smad signalling pathway compared with hADSC-CM. Conclusions hFDSPC-CM combined with HA was superior for treating diabetic wounds. The underlying mechanism may promote proliferation and migration of epidermal cells with fibroblasts, thus leading to ECM deposition and remodelling. Reduced inflammation may be due to the above-mentioned mechanism.

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Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation

Cited by 208 publications

References 133 publications

Bioinformatic Analysis of Key Genes and Pathways Related to Keloids

Bioinformatic Analysis of Key Genes and Pathways Related to Keloids

TGF-β Pathway in Salivary Gland Fibrosis

Human foreskin-derived dermal stem/progenitor cell-conditioned medium combined with hyaluronic acid promotes extracellular matrix regeneration in diabetic wounds

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