Role and regulatory factors of fibroblasts in hypertrophic scar formation

doi:10.3877/cma.j.issn.1673-9450.2023.01.013

Abstract

Abstract:

Hypertrophic scars are the result of excessive deposition of extracellular matrix(ECM) components, which have a significant impact on the patient′s quality of life. Fibroblasts play an integral role in both normal wound healing and hypertrophic scarring. Fibroblasts are regulated by a variety of cell growth factors in the process of promoting scarring which play their roles through different signaling pathways. Elucidating the relationship between the above factors or pathways and hypertrophic scar may contribute to the development of new drugs and the treatment of hypertrophic scar. This article summarizes the mechanism of hypertrophic scarring, clarifies the function of fibroblasts and the role of growth factors secreted by them in hypertrophic scarring, and briefly summarizes the signaling pathways involved in scarring-related growth factors, providing a new direction for the treatment of hypertrophic scars.

Key words: Fibroblasts, Cicatrix, Extracellular matrix, Growth factors, Signaling pathways

Yimiao Wang, Peijie He. Role and regulatory factors of fibroblasts in hypertrophic scar formation[J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2023, 18(01): 78-85.

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References 63

[1]	Reinke JM, Sorg H. Wound repair and regeneration[J]. Eur Surg Res, 2012, 49(1): 35-43.
[2]	Scharf GM, Kilian K, Cordero J, et al. Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation[J]. JCI Insight, 2019, 5(15): e126721.
[3]	Coentro JQ, Pugliese E, Hanley G, et al. Current and upcoming therapies to modulate skin scarring and fibrosis[J]. Adv Drug Deliv Rev, 2019, 146: 37-59.
[4]	Xie J, Yao B, Han Y, et al. Skin appendage-derived stem cells: cell biology and potential for wound repair[J]. Burns Trauma, 2016, 4: 38.
[5]	Berman B, Maderal A, Raphael B. Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment[J]. Dermatol Surg, 2017, 43 Suppl 1: S3-S18.
[6]	Andrews JP, Marttala J, Macarak E, et al. Keloids: The paradigm of skin fibrosis - Pathomechanisms and treatment[J]. Matrix Biol, 2016, 51: 37-46.
[7]	Sorrell JM, Caplan AI. Fibroblasts-a diverse population at the center of it all[J]. Int Rev Cell Mol Biol, 2009, 276: 161-214.
[8]	Lian N, Li T. Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications[J]. Biomed Pharmacother, 2016, 84: 42-50.
[9]	Schulz JN, Plomann M, Sengle G, et al. New developments on skin fibrosis - Essential signals emanating from the extracellular matrix for the control of myofibroblasts[J]. Matrix Biol, 2018, 68-69: 522-532.
[10]	Mora-Navarro C, Badileanu A, Gracioso AM, et al. Porcine Vocal Fold Lamina Propria-Derived Biomaterials Modulate TGF-beta1-Mediated Fibroblast Activation in Vitro[J]. ACS Biomater Sci Eng, 2020, 6(3): 1690-1703.
[11]	Janson DG, Saintigny G, van Adrichem A, et al. Different gene expression patterns in human papillary and reticular fibroblasts[J]. J Invest Dermatol, 2012, 132(11): 2565-2572.
[12]	Hinz B, Gabbiani G. Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives[J]. F1000 Biol Rep, 2010, 2: 78.
[13]	Tan J, Wu J. Current progress in understanding the molecular pathogenesis of burn scar contracture[J]. Burns Trauma, 2017, 5: 14.
[14]	Rodrigues M, Kosaric N, Bonham CA, et al. Wound Healing: A Cellular Perspective[J]. Physiol Rev, 2019, 99(1): 665-706.
[15]	Desmoulière A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar[J]. Am J Pathol, 1995, 146(1): 56-66.
[16]	Khansa I, Harrison B, Janis JE. Evidence-Based Scar Management: How to Improve Results with Technique and Technology[J]. Plast Reconstr Surg, 2016, 138(3 Suppl): 165S-178S.
[17]	Zhu Z, Ding J, Tredget EE. The molecular basis of hypertrophic scars[J]. Burns Trauma, 2016, 4: 2.
[18]	Le M, Naridze R, Morrison J, et al. Transforming growth factor Beta 3 is required for excisional wound repair in vivo[J]. PLoS One, 2012, 7(10): e48040.
[19]	Buscemi L, Ramonet D, Klingberg F, et al. The single-molecule mechanics of the latent TGF-beta1 complex[J]. Curr Biol, 2011, 21(24): 2046-2054.
[20]	Hinz B. The role of myofibroblasts in wound healing[J]. Curr Res Transl Med, 2016, 64(4): 171-177.
[21]	Chang Z, Kishimoto Y, Hasan A, et al. TGF-beta3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats[J]. Dis Model Mech, 2014, 7(1): 83-91.
[22]	Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs[J]. Cardiovasc Res, 2006, 69(3): 562-573.
[23]	Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteolysis[J]. Matrix Biol, 2015, 44-46: 247-254.
[24]	Rousseau B, Ge PJ, Ohno T, et al. Extracellular matrix gene expression after vocal fold injury in a rabbit model[J]. Ann Otol Rhinol Laryngol, 2008, 117(8): 598-603.
[25]	Meng X, Zhang K, Kong J, et al. Deletion of resistin-like molecule-beta attenuates angiotensin II-induced abdominal aortic aneurysm[J]. Oncotarget, 2017, 8(61): 104171-104181.
[26]	Kopcewicz MM, Kur-Piotrowska A, Bukowska J, et al. Foxn1 and Mmp-9 expression in intact skin and during excisional wound repair in young, adult, and old C57Bl/6 mice[J]. Wound Repair Regen, 2017, 25(2): 248-259.
[27]	Guimaraes-Stabili MR, de Medeiros MC, Rossi D, et al. Silencing matrix metalloproteinase-13 (Mmp-13) reduces inflammatory bone resorption associated with LPS-induced periodontal disease in vivo[J]. Clin Oral Investig, 2021, 25(5): 3161-3172.
[28]	Wang J, Zhang N, Peng M, et al. p85alpha Inactivates MMP-2 and Suppresses Bladder Cancer Invasion by Inhibiting MMP-14 Transcription and TIMP-2 Degradation[J]. Neoplasia, 2019, 21(9): 908-920.
[29]	Wang XQ, Song F, Liu YK. Hypertrophic scar regression is linked to the occurrence of endothelial dysfunction[J]. PLoS One, 2017, 12(5): e176681.
[30]	Karsdal MA, Nielsen SH, Leeming DJ, et al. The good and the bad collagens of fibrosis - Their role in signaling and organ function[J]. Adv Drug Deliv Rev, 2017, 121: 43-56.
[31]	Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA[J]. Dev Cell, 2014, 31(6): 722-733.
[32]	De Donatis A, Comito G, Buricchi F, et al. Proliferation versus migration in platelet-derived growth factor signaling: the key role of endocytosis[J]. J Biol Chem, 2008, 283(29): 19948-19956.
[33]	Wågsäter D, Zhu C, Björck HM, et al. Effects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression[J]. Atherosclerosis, 2009, 202(2): 415-423.
[34]	Klinkhammer BM, Floege J, Boor P. PDGF in organ fibrosis[J]. Mol Aspects Med, 2018, 62: 44-62.
[35]	Ikawa T, Ichimura Y, Miyagawa T, et al. The Contribution of LIGHT to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts[J]. J Invest Dermatol, 2022, 142(6): 1541-1551.e3.
[36]	Bosurgi L, Cao YG, Cabeza-Cabrerizo M, et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells[J]. Science, 2017, 356(6342): 1072-1076.
[37]	Braune J, Weyer U, Hobusch C, et al. IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity[J]. J Immunol, 2017, 198(7): 2927-2934.
[38]	Dufour AM, Alvarez M, Russo B, et al. Interleukin-6 and Type-I Collagen Production by Systemic Sclerosis Fibroblasts Are Differentially Regulated by Interleukin-17A in the Presence of Transforming Growth Factor-Beta 1[J]. Front Immunol, 2018, 9: 1865.
[39]	Nicoletti G, Saler M, Villani L, et al. Platelet Rich Plasma Enhancement of Skin Regeneration in an ex-vivo Human Experimental Model[J]. Front Bioeng Biotechnol, 2019, 7: 2.
[40]	Goodarzi P, Falahzadeh K, Nematizadeh M, et al. Tissue Engineered Skin Substitutes[J]. Adv Exp Med Biol, 2018, 1107: 143-188.
[41]	Chun Q, ZhiYong W, Fei S, et al. Dynamic biological changes in fibroblasts during hypertrophic scar formation and regression[J]. Int Wound J, 2016, 13(2): 257-262.
[42]	Wilgus TA, Ferreira AM, Oberyszyn TM, et al. Regulation of scar formation by vascular endothelial growth factor[J]. Lab Invest, 2008, 88(6): 579-590.
[43]	Hirabayashi M, Asano Y, Yamashita T, et al. Possible pro-inflammatory role of heparin-binding epidermal growth factor-like growth factor in the active phase of systemic sclerosis[J]. J Dermatol, 2018, 45(2): 182-188.
[44]	Park CH, Chung JH. Epidermal growth factor-induced matrix metalloproteinase-1 expression is negatively regulated by p38 MAPK in human skin fibroblasts[J]. J Dermatol Sci, 2011, 64(2): 134-141.
[45]	Hong JP, Park SW. The combined effect of recombinant human epidermal growth factor and erythropoietin on full-thickness wound healing in diabetic rat model[J]. Int Wound J, 2014, 11(4): 373-378.
[46]	Richard JL, Parer-Richard C, Daures JP, et al. Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot, randomized, double-blind, placebo-controlled study[J]. Diabetes Care, 1995, 18(1): 64-69.
[47]	Thew J, Burrage P, Medlicott N, et al. Modelling optimal delivery of bFGF to chronic wounds using ODEs[J]. J Theor Biol, 2019, 465: 109-116.
[48]	Abdelhakim M, Lin X, Ogawa R. The Japanese Experience with Basic Fibroblast Growth Factor in Cutaneous Wound Management and Scar Prevention: A Systematic Review of Clinical and Biological Aspects[J]. Dermatol Ther (Heidelb), 2020, 10(4): 569-587.
[49]	Kawai Y, Kishimoto Y, Sogami T, et al. Characterization of aged rat vocal fold fibroblasts[J]. Laryngoscope, 2019, 129(3): E94-E101.
[50]	Akasaka Y, Ono I, Kamiya T, et al. The mechanisms underlying fibroblast apoptosis regulated by growth factors during wound healing[J]. J Pathol, 2010, 221(3): 285-299.
[51]	Hirano S, Sugiyama Y, Kaneko M, et al. Intracordal Injection of Basic Fibroblast Growth Factor in 100 Cases of Vocal Fold Atrophy and Scar[J]. Laryngoscope, 2021, 131(9): 2059-2064.
[52]	Mori T, Yoshida M, Hazekawa M, et al. Antimicrobial Activities of LL-37 Fragment Mutant-Poly (Lactic-Co-Glycolic) Acid Conjugate against Staphylococcus aureus, Escherichia coli, and Candida albicans[J]. Int J Mol Sci, 2021, 22(10): 5097.
[53]	Zhao W, Han Q, Lin H, et al. Improved neovascularization and wound repair by targeting human basic fibroblast growth factor (bFGF) to fibrin[J]. J Mol Med (Berl), 2008, 86(10): 1127-1138.
[54]	Xu F, Liu C, Zhou D, et al. TGF-beta/SMAD Pathway and Its Regulation in Hepatic Fibrosis[J]. J Histochem Cytochem, 2016, 64(3): 157-167.
[55]	Xu J, Shao T, Song M, et al. MIR22HG acts as a tumor suppressor via TGFbeta/SMAD signaling and facilitates immunotherapy in colorectal cancer[J]. Mol Cancer, 2020, 19(1): 51.
[56]	Yu DK, Zhang CX, Zhao SS, et al. The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway[J]. Acta Pharmacol Sin, 2015, 36(4): 473-482.
[57]	Ackers I, Malgor R. Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases[J]. Diab Vasc Dis Res, 2018, 15(1): 3-13.
[58]	Gajos-Michniewicz A, Czyz M. WNT Signaling in Melanoma[J]. Int J Mol Sci, 2020, 21(14): 4852.
[59]	Xiao L, Zhou D, Tan RJ, et al. Sustained Activation of Wnt/beta-Catenin Signaling Drives AKI to CKD Progression[J]. J Am Soc Nephrol, 2016, 27(6): 1727-1740.
[60]	Chen H, Yang T, Wang MC, et al. Novel RAS inhibitor 25-O-methylalisol F attenuates epithelial-to-mesenchymal transition and tubulo-interstitial fibrosis by selectively inhibiting TGF-beta-mediated Smad3 phosphorylation[J]. Phytomedicine, 2018, 42: 207-218.
[61]	Edeling M, Ragi G, Huang S, et al. Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog[J]. Nat Rev Nephrol, 2016, 12(7): 426-439.
[62]	Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis[J]. Nat Rev Nephrol, 2016, 12(6): 325-338.
[63]	Vallée A, Guillevin R, Vallée JN. Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/beta-catenin pathway in gliomas[J]. Rev Neurosci, 2018, 29(1): 71-91.

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