Hypoxia drives the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the TGF-β1/Smad3 pathway Corrigendum in /10.3892/ijmm.2019.4403

Zhao,Bin; Guan,Hao; Liu,Jia-Qi; Zheng,Zhao; Zhou,Qin; Zhang,Jian; Su,Lin-Lin; Hu,Da-Hai

doi:10.3892/ijmm.2016.2816

Hypoxia drives the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the TGF-β1/Smad3 pathway

Corrigendum in: /10.3892/ijmm.2019.4403

Authors:
- Bin Zhao
- Hao Guan
- Jia-Qi Liu
- Zhao Zheng
- Qin Zhou
- Jian Zhang
- Lin-Lin Su
- Da-Hai Hu
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Affiliations: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: December 1, 2016 https://doi.org/10.3892/ijmm.2016.2816
Pages: 153-159
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Keloids, partially considered as benign tumors, are characterized by the overgrowth of fibrosis beyond the boundaries of the wound and are regulated mainly by transforming growth factor (TGF)-β1, which induces the transition of fibroblasts to myofibroblasts. Hypoxia is an important driving force in the development of lung and liver fibrosis by activating hypoxia inducible factor-1α and stimulating epithelial‑mesenchymal transition. However, it is unknown whether and hypoxia can influence human dermal scarring. The aim of this study was to investigate whether hypoxia drives the transition of dermal fibroblasts to myofibroblasts and to clarify the potential transduction mechanisms involved. First, we observed that keloids are a relatively hypoxic tissue. Second, we found that hypoxia drives the transition of normal dermal fibroblasts to a myofibroblast-like phenotype [high expression of α-smooth muscle actin (α-SMA) and collagen I and III]. Finally, hypoxia effectively facilitated the nuclear import of the Smad2 and Smad3 complex, while blockade with the Smad3 inhibitor, SIS3, significantly impaired the expression of hypoxia-induced fibrosis-related molecules. Taken together, to the best of our knowledge, this study demonstrates for the first time that hypoxia facilitates the transition of dermal fibroblasts to myofibroblasts through the activation of the TGF-β1/Smad3 signaling pathway and our findings may provide a potential target for the treatment of keloids.

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1	Bran GM, Goessler UR, Hormann K, Riedel F and Sadick H: Keloids: current concepts of pathogenesis (Review). Int J Mol Med. 24:283–293. 2009. View Article : Google Scholar : PubMed/NCBI
2	Meyer LJ, Russell SB, Russell JD, Trupin JS, Egbert BM, Shuster S and Stern R: Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts. J Invest Dermatol. 114:953–959. 2000. View Article : Google Scholar : PubMed/NCBI
3	Daian T, Ohtsuru A, Rogounovitch T, Ishihara H, Hirano A, Akiyama-Uchida Y, Saenko V, Fujii T and Yamashita S: Insulin-like growth factor-I enhances transforming growth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. J Invest Dermatol. 120:956–962. 2003. View Article : Google Scholar : PubMed/NCBI
4	Dong X, Mao S and Wen H: Upregulation of proinflammatory genes in skin lesions may be the cause of keloid formation (Review). Biomed Rep. 1:833–836. 2013.
5	Olman MA: Beyond TGF-beta: a prostaglandin promotes fibrosis. Nat Med. 15:1360–1361. 2009. View Article : Google Scholar : PubMed/NCBI
6	Ong CT, Khoo YT, Mukhopadhyay A, Do DV, Lim IJ, Aalami O and Phan TT: mTOR as a potential therapeutic target for treatment of keloids and excessive scars. Exp Dermatol. 16:394–404. 2007. View Article : Google Scholar : PubMed/NCBI
7	Zhan L, Huang C, Meng XM, Song Y, Wu XQ, Yang Y and Li J: Hypoxia-inducible factor-1alpha in hepatic fibrosis: a promising therapeutic target. Biochimie. 108:1–7. 2015. View Article : Google Scholar
8	O'Connell MP and Weeraratna AT: Change is in the air: the hypoxic induction of phenotype switching in melanoma. J Invest Dermatol. 133:2316–2317. 2013. View Article : Google Scholar : PubMed/NCBI
9	Zhang Z, Nie F, Kang C, Chen B, Qin Z, Ma J, Ma Y and Zhao X: Increased periostin expression affects the proliferation, collagen synthesis, migration and invasion of keloid fibroblasts under hypoxic conditions. Int J Mol Med. 34:253–261. 2014.PubMed/NCBI
10	Cash TP, Pan Y and Simon MC: Reactive oxygen species and cellular oxygen sensing. Free Radic Biol Med. 43:1219–1225. 2007. View Article : Google Scholar : PubMed/NCBI
11	Gaber T, Dziurla R, Tripmacher R, Burmester GR and Buttgereit F: Hypoxia inducible factor (HIF) in rheumatology: low O₂! See what HIF can do! Ann Rheum Dis. 64:971–980. 2005. View Article : Google Scholar : PubMed/NCBI
12	Zhang Q, Wu Y, Ann DK, Messadi DV, Tuan TL, Kelly AP, Bertolami CN and Le AD: Mechanisms of hypoxic regulation of plasminogen activator inhibitor-1 gene expression in keloid fibroblasts. J Invest Dermatol. 121:1005–1012. 2003. View Article : Google Scholar
13	Ueda K, Yasuda Y, Furuya E and Oba S: Inadequate blood supply persists in keloids. Scand J Plast Reconstr Surg Hand Surg. 38:267–271. 2004. View Article : Google Scholar : PubMed/NCBI
14	Steinbrech DS, Mehrara BJ, Chau D, Rowe NM, Chin G, Lee T, Saadeh PB, Gittes GK and Longaker MT: Hypoxia upregulates VEGF production in keloid fibroblasts. Ann Plast Surg. 42:514–519; discussion 519–520. 1999. View Article : Google Scholar : PubMed/NCBI
15	Ruthenborg RJ, Ban JJ, Wazir A, Takeda N and Kim JW: Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Mol Cells. 37:637–643. 2014. View Article : Google Scholar : PubMed/NCBI
16	Lebrin F, Deckers M, Bertolino P and Ten Dijke P: TGF-beta receptor function in the endothelium. Cardiovasc Res. 65:599–608. 2005. View Article : Google Scholar : PubMed/NCBI
17	Santibañez JF, Quintanilla M and Bernabeu C: TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 121:233–251. 2011. View Article : Google Scholar
18	Jinnin M, Ihn H and Tamaki K: Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 69:597–607. 2006. View Article : Google Scholar
19	Liu J, Wang Y, Pan Q, Su Y, Zhang Z, Han J, Zhu X, Tang C and Hu D: Wnt/β-catenin pathway forms a negative feedback loop during TGF-β1 induced human normal skin fibroblast-to-myofibroblast transition. J Dermatol Sci. 65:38–49. 2012. View Article : Google Scholar
20	Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C and Brown RA: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 3:349–363. 2002. View Article : Google Scholar : PubMed/NCBI
21	Desmoulière A, Chaponnier C and Gabbiani G: Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 13:7–12. 2005. View Article : Google Scholar : PubMed/NCBI
22	Hinz B, Celetta G, Tomasek JJ, Gabbiani G and Chaponnier C: Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 12:2730–2741. 2001. View Article : Google Scholar : PubMed/NCBI
23	Zhang Z, Nie F, Chen X, Qin Z, Kang C, Chen B, Ma J, Pan B and Ma Y: Upregulated periostin promotes angiogenesis in keloids through activation of the ERK 1/2 and focal adhesion kinase pathways, as well as the upregulated expression of VEGF and angiopoietin 1. Mol Med Rep. 11:857–864. 2015.
24	Jiang HS, Zhu LL, Zhang Z, Chen H, Chen Y and Dai YT: Estradiol attenuates the TGF-β1-induced conversion of primary TAFs into myofibroblasts and inhibits collagen production and myofibroblast contraction by modulating the Smad and Rho/Rock signaling pathways. Int J Mol Med. 36:801–807. 2015.PubMed/NCBI
25	Bosco MC, Puppo M, Blengio F, Fraone T, Cappello P, Giovarelli M and Varesio L: Monocytes and dendritic cells in a hypoxic environment: spotlights on chemotaxis and migration. Immunobiology. 213:733–749. 2008. View Article : Google Scholar : PubMed/NCBI
26	Sen CK and Roy S: Oxygenation state as a driver of myofibroblast differentiation and wound contraction: hypoxia impairs wound closure. J Invest Dermatol. 130:2701–2703. 2010. View Article : Google Scholar : PubMed/NCBI
27	Nauta TD, van Hinsbergh VW and Koolwijk P: Hypoxic signaling during tissue repair and regenerative medicine. Int J Mol Sci. 15:19791–19815. 2014. View Article : Google Scholar : PubMed/NCBI
28	Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiaro PA and Semenza GL: Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res. 93:1074–1081. 2003. View Article : Google Scholar : PubMed/NCBI
29	Haase VH: Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int. 76:492–499. 2009. View Article : Google Scholar : PubMed/NCBI
30	Sloan DF, Brown RD, Wells CH and Hilton JG: Tissue gases in human hypertrophic burn scars. Plast Reconstr Surg. 61:431–436. 1978. View Article : Google Scholar : PubMed/NCBI
31	Zavadil J and Böttinger EP: TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 24:5764–5774. 2005. View Article : Google Scholar : PubMed/NCBI
32	Copple BL: Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int. 30:669–682. 2010. View Article : Google Scholar : PubMed/NCBI
33	Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C, Phelan D, Ledwidge MT, McDonald KM, McCann A, et al: Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet. 23:2176–2188. 2014. View Article : Google Scholar
34	Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, et al: Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 19:1617–1624. 2013. View Article : Google Scholar : PubMed/NCBI