Advances in understanding the mechanism of wound scar formation

Expand
  • School of Medicine, Shanghai University, Shanghai 200444, China

Received date: 2022-07-27

  Online published: 2022-11-12

Abstract

The skin is the first line of the protective barrier that is constantly exposed to various insults, such as physical and chemical factors, microbes, and pathogens, often causing skin injuries. The healing of injured skin is a highly dynamic and organized process orchestrated by the interactions of various cell types, cytokines, and extracellular matrix. However, chronic inflammation and excessive collagen synthesis during wound healing can develop skin fibrosis, eventually becoming a permanent scar. Fibrotic skin or scarring frequently compromises skin function and causes mental trauma, physical pain, and a heavy financial burden. Despite this, specific and effective anti-scarring drugs are still lacking in clinical practice. Over the past several years, studies using mouse models, signal cell analysis, and lineage tracing techniques have unraveled significant molecular mechanisms underlying scar formation. This review discusses the latest research advances on scar formation during skin repair. Further study of the scar formation mechanisms will provide novel insights into the possible development of anti-scar and tissue-regeneration drugs.

Cite this article

DOU Hanyu, CUI Baiping, DING Xiaolei . Advances in understanding the mechanism of wound scar formation[J]. Journal of Shanghai University, 2022 , 28(5) : 831 -840 . DOI: 10.12066/j.issn.1007-2861.2442

References

[1] Proksch E, Brandner J M, Jensen J M. The skin: an indispensable barrier[J]. Experimental dermatology, 2008, 17: 1063-1072.
[2] Rodrigues M, Kosaric N, Bonham C A, et al. Wound healing: a cellular perspective[J]. Physiological Reviews, 2019, 99: 665-706.
[3] Sen C K, Gordillo G M, Roy S, et al. Human skin wounds: a major and snowballing threat to public health and the economy[J]. Wound Repair and Regeneration. 2009, 17: 763-771.
[4] Chesko D M, Wilgus T A. Immune cells in cutaneous wound healing: a review of functional data from animal models[J]. International Journal of Molecular Sciences, 2022, 23(5): 2044.
[5] Feng Y, Sun Z L, Liu S Y, et al. Direct and indirect roles of macrophages in hypertrophic scar formation[J]. Frontiers in Physiology, 2019, 10: 1101.
[6] Buechler M B, Fu W, Turley S J. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer[J]. Immunity, 2021, 54: 903-915.
[7] Longaker M T, Whitby D J, Adzick N S, et al. Studies in fetal wound healing, Ⅵ. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation[J]. Journal of Pediatric Surgery, 1990, 25: 63-68.
[8] Marshall C D, Hu M S, Leavitt T, et al. Cutaneous scarring: basic science, current treatments, and future directions[J]. Advances in Wound Care, 2018, 7: 29-45.
[9] Rinkevich Y, Walmsley G G, Hu M S, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential[J]. Science, 2015, 348: aaa2151.
[10] Horsley V. Cut out that YAPping: mechanisms to reduce scar formation[J]. Cell Stem Cell, 2022, 29: 179-181.
[11] Mascharak S, Des Jardins-Park H E, Davitt M F, et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring[J]. Science, 2021, 372(6540): eaba2374.
[12] Mascharak S, Talbott H E, Januszyk M, et al. Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing[J]. Cell Stem Cell, 2022, 29: 315-327.
[13] Philippeos C, Telerman S B, Oulès B, et al. Spatial and single-cell transcriptional profiling identifies functionally distinct human dermal fibroblast subpopulations[J]. The Journal of Investigative Dermatology, 2018, 138: 811-825.
[14] He H, Suryawanshi H, Morozov P, et al. Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis[J]. The Journal of Allergy and Clinical Immunology, 2020, 145: 1615-1628.
[15] Harper R A, Grove G. Human skin fibroblasts derived from papillary and reticular dermis: differences in growth potential in vitro[J]. Science, 1979, 204: 526-527.
[16] Janson D G, Saintigny G, Van Adrichem A, et al. Different gene expression patterns in human papillary and reticular fibroblasts[J]. The Journal of Investigative Dermatology, 2012, 132: 2565-2572.
[17] Driskell R R, Lichtenberger B M, Hoste E, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair[J]. Nature, 2013, 504: 277-281.
[18] Gauglitz G G, Korting H C, Pavicic T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies[J]. Molecular Medicine, 2011, 17: 113-125.
[19] Gabbiani G, Ryan G B, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction[J]. Experientia, 1971, 27: 549-550.
[20] Hinz B. The role of myofibroblasts in wound healing[J]. Current Research in Translational Medicine, 2016, 64: 171-177.
[21] Hinz B, Gabbiani G. Mechanisms of force generation and transmission by myofibroblasts[J]. Current Opinion in Biotechnology, 2003, 14: 538-546.
[22] Padmanabhan J, Maan Z N, Kwon S H, et al. In vivo models for the study of fibrosis[J]. Advances in Wound Care, 2019, 8: 645-654.
[23] Sakar M S, Eyckmans J, Pieters R, et al. Cellular forces and matrix assembly coordinate fibrous tissue repair[J]. Nature Communications, 2016, 7: 11036.
[24] Zhao X K, Cheng Y, Liang C M, et al. Focal adhesion kinase regulates fibroblast migration via integrin beta-1 and plays a central role in fibrosis[J]. Scientific Reports, 2016, 6: 19276.
[25] Jiang D, Christ S, Correa-Gallegos D, et al. Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin[J]. Nature Communications, 2020, 11: 5653.
[26] Takeichi M. Cadherins: a molecular family important in selective cell-cell adhesion[J]. Annual Review of Biochemistry, 1990, 59: 237-252.
[27] Wan L, Jiang D, Correa-Gallegos D, et al. Connexin 43 gap junction drives fascia mobilization and repair of deep skin wounds[J]. Matrix Biology : Journal of the International Society for Matrix Biology, 2021, 97: 58-71.
[28] Kotini M, Barriga E H, Leslie J, et al. Gap junction protein Connexin-43 is a direct transcriptional regulator of N-cadherin in vivo[J]. Nature Communications, 2018, 9: 3846.
[29] Li X, Guo L, Yang X, et al. TGF-$\beta $1-induced connexin43 promotes scar formation via the Erk/MMP-1/collagen Ⅲ pathway[J]. Journal of Oral Rehabilitation, 2020, 47: 99-106.
[30] Mosser D M, Edwards J P. Exploring the full spectrum of macrophage activation[J]. Nature Reviews Immunology, 2008, 8: 958-969.
[31] Wei S, Chow L T, Shum I O, et al. Left and right ventricular collagen type Ⅰ/Ⅲ ratios and remodeling post-myocardial infarction[J]. Journal of Cardiac Failure, 1999, 5: 117-126.
[32] Davies L C, Taylor P R. Tissue-resident macrophages: then and now[J]. Immunology, 2015, 144: 541-548.
[33] Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system[J]. Nature Immunology, 2015, 16: 343-353.
[34] Willenborg S, Lucas T, Van Loo G, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair[J]. Blood, 2012, 120: 613-625.
[35] Hesketh M, Sahin K B, West Z E, et al. Macrophage phenotypes regulate scar formation and chronic wound healing[J]. International Journal of Molecular Sciences, 2017, 18(7): 1545.
[36] Knipper J A, Willenborg S, Brinckmann J, et al. Interleukin-4 receptor $\alpha $ signaling in myeloid cells controls collagen fibril assembly in skin repair[J]. Immunity, 2015, 43: 803-816.
[37] Sindrilaru A, Peters T, Wieschalka S, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice[J]. The Journal of Clinical Investigation, 2011, 121: 985-997.
[38] Herold S, Mayer K, Lohmeyer J. Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair[J]. Frontiers in Immunology, 2011, 2: 65.
[39] Khallou-Laschet J, Varthaman A, Fornasa G, et al. Macrophage plasticity in experimental atherosclerosis[J]. PLoS One, 2010, 5: e8852.
[40] Anderson-Baucum E, Pi?eros A R, Kulkarni A, et al. Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype[J]. Cell Metabolism, 2021, 33: 1883-1893.
[41] Kraakman M J, Murphy A J, Jandeleit-Dahm K, et al. Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function?[J]. Frontiers in Immunology, 2014, 5: 470.
[42] Vannella K M, Wynn T A. Mechanisms of organ injury and repair by macrophages[J]. Annual Review of Physiology, 2017, 79: 593-617.
[43] Das A, Sinha M, Datta S, et al. Monocyte and macrophage plasticity in tissue repair and regeneration[J]. The American Journal of Pathology, 2015, 185: 2596-2606.
[44] Zhu Y, Li X, Chen J, et al. The pentacyclic triterpene Lupeol switches M1 macrophages to M2 and ameliorates experimental inflammatory bowel disease[J]. International Immunopharmacology, 2016, 30: 74-84.
[45] Chen L, Li Z, Zheng Y, et al. 3D-printed dermis-specific extracellular matrix mitigates scar contraction via inducing early angiogenesis and macrophage M2 polarization[J]. Bioactive Materials, 2022, 10: 236-246.
[46] Kurose H, Mangmool S. Myofibroblasts and inflammatory cells as players of cardiac fibrosis[J]. Archives of Pharmacal Research, 2016, 39: 1100-1113.
[47] Zhu Z, Ding J, Ma Z, et al. Systemic depletion of macrophages in the subacute phase of wound healing reduces hypertrophic scar formation[J]. Wound Repair and Regeneration, 2016, 24: 644-656.
[48] Funes S C, Rios M, Escobar-Vera J, et al. Implications of macrophage polarization in autoimmunity[J]. Immunology, 2018, 154: 186-195.
[49] Goren I, Allmann N, Yogev N, et al. A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes[J]. The American Journal of Pathology, 2009, 175: 132-147.
[50] Franz S, Ertel A, Engel K M, et al. Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NF$\kappa$B-signaling worsening inflammation and wound healing[J]. Theranostics, 2022, 12: 1659-1682.
Outlines

/