Biophysical approach to studying protein interactions in skin wound healing
Article Sidebar
Main Article Content
Abstract
Cutaneous wounds are a significant health problem worldwide. That is why wound healing and biological factors, including proteins, are substantial. This complicated and dynamic process consists of five overlapping phases: Hemostasis, Inflammation, Granulation tissue formation, Re-epithelialization, and Remodeling. Cells and proteins shared in these phases can trigger myriad activities that eventually complement each other. This paper aims to provide an understanding of the key proteins' functions and signaling involved in the wound healing process, based on data available on bioinformatics websites. These proteins include the interleukin-1 family, tight junction proteins (occludin and claudin), platelet-derived growth factor (PDGF), and extracellular matrix components such as matrix metalloproteinases (MMPs), fibronectin, and laminins. In addition, by examining the significant role of inflammatory cytokines, proteases, and members of the large family of metalloproteinases, we can take novel measures to accelerate the healing of chronic wounds that are stuck in the inflammatory phase. Additionally, it is notable that mediator proteins are vital, as they exhibit co-expression and share molecular interactions with key proteins. Therefore, their absence or impaired functioning can disrupt the normal healing process of skin wounds.
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
References
[1] Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haught R, Nusgart M, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value Health. 2018;21(1):27-32.
DOI: 10.1016/j.jval.2017.07.007 PMID: 29304937
[2] Sen CK. Human Wounds and Its Burden: An Updated Compendium of Estimates. Adv Wound Care (New Rochelle). 2019;8(2):39-48. DOI: 10.1089/wound.2019.0946
PMID: 30809421
[3] Sen CK. Human Wound and Its Burden: Updated 2020 Compendium of Estimates. Adv Wound Care (New Rochelle). 2021;10(5):281-292. DOI: 10.1089/wound.2021.0026
PMID: 33733885
[4] Rogers LC, Armstrong DG, Capotorto J, Fife CE, Garcia JR, Gelly H, et al. Wound Center Without Walls: The New Model of Providing Care During the COVID-19 Pandemic. Wounds. 2020;32(7):178-185. PMID: 32335520
[5] Nejati R, Kovacic D, Slominski A. Neuro-immune-endocrine functions of the skin: an overview. Expert Rev Dermatol. 2013;8(6):581-583. DOI: 10.1586/17469872.2013.856690 PMID: 24587812
[6] Tottoli EM, Dorati R, Genta I, Chiesa E, Pisani S, Conti B. Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration. Pharmaceutics. 2020;12(8):735. DOI: 10.3390/pharmaceutics12080735
PMID: 32764269
[7] Yousef H, Miao JH, Alhajj M, Badri T. Histology, Skin Appendages. 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 29489291
[8] Marcos-Garcés V, Molina Aguilar P, Bea Serrano C, García Bustos V, Benavent Seguí J, Ferrández Izquierdo A, et al. Age-related dermal collagen changes during development, maturation and ageing - a morphometric and comparative study. J Anat. 2014;225(1):98-108. DOI: 10.1111/joa.12186 PMID: 24754576
[9] Rippa AL, Kalabusheva EP, Vorotelyak EA. Regeneration of Dermis: Scarring and Cells Involved. Cells. 2019;8(6):607.
DOI: 10.3390/cells8060607 PMID: 31216669
[10] Lansdown AB. Calcium: a potential central regulator in wound healing in the skin. Wound Repair Regen. 2002;10(5):271-85. DOI: 10.1046/j.1524-475x.2002.10502.x PMID: 12406163
[11] Gao FL, Jin R, Zhang L, Zhang YG. The contribution of melanocytes to pathological scar formation during wound healing. Int J Clin Exp Med. 2013;6(7):609-13. PMID: 23936604
[12] Roh JS, Sohn DH. Damage-Associated Molecular Patterns in Inflammatory Diseases. Immune Netw. 2018;18(4):e27.
DOI: 10.4110/in.2018.18.e27 PMID: 30181915
[13] van der Vliet A, Janssen-Heininger YM. Hydrogen peroxide as a damage signal in tissue injury and inflammation: murderer, mediator, or messenger? J Cell Biochem. 2014;115(3):427-35. DOI: 10.1002/jcb.24683 PMID: 24122865
[14] Ozgok Kangal MK, Regan JP. Wound Healing. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.
URL: https://www.ncbi.nlm.nih.gov/books/NBK535406
[15] Cañedo-Dorantes L, Cañedo-Ayala M. Skin Acute Wound Healing: A Comprehensive Review. Int J Inflam. 2019;2019:3706315. DOI: 10.1155/2019/3706315
PMID: 31275545
[16] Wilkinson HN, Hardman MJ. Wound healing: cellular mechanisms and pathological outcomes. Open Biol. 2020;10(9):200223. DOI: 10.1098/rsob.200223
PMID: 32993416
[17] Schultz GS, Chin GA, Moldawer L, Diegelmann RF. Principles of Wound Healing. In: Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011. PMID: 30485016
[18] Sorrentino S, Studt JD, Medalia O, Tanuj Sapra K. Roll, adhere, spread and contract: structural mechanics of platelet function. Eur J Cell Biol. 2015;94(3-4):129-38.
DOI: 10.1016/j.ejcb.2015.01.001 PMID: 25655000
[19] Litvinov RI, Pieters M, de Lange-Loots Z, Weisel JW. Fibrinogen and Fibrin. Subcell Biochem. 2021;96:471-501.
DOI: 10.1007/978-3-030-58971-4_15 PMID: 33252741
[20] Wallace HA, Basehore BM, Zito PM. Wound Healing Phases. 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 29262065
[21] Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med. 2009;6(1):16-26. DOI: 10.1038/ncpcardio1397 PMID: 19029993
[22] Toriseva M, Kähäri VM. Proteinases in cutaneous wound healing. Cell Mol Life Sci. 2009;66(2):203-24. DOI: 10.1007/s00018-008-8388-4 PMID: 18810321
[23] Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O. Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol. 2005;83(2):196-8. DOI: 10.1111/j.1440-1711.2005.01314.x PMID: 15748217
[24] Gantwerker EA, Hom DB. Skin: histology and physiology of wound healing. Facial Plast Surg Clin North Am. 2011;19(3):441-53. DOI: 10.1016/j.fsc.2011.06.009
PMID: 21856533
[25] Shah D, Mital K. The Role of Trypsin:Chymotrypsin in Tissue Repair. Adv Ther. 2018;35(1):31-42. DOI: 10.1007/s12325-017-0648-y PMID: 29209994
[26] Shah JM, Omar E, Pai DR, Sood S. Cellular events and biomarkers of wound healing. Indian J Plast Surg. 2012;45(2):220-8. DOI: 10.4103/0970-0358.101282
PMID: 23162220
[27] Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35-43. DOI: 10.1159/000339613
PMID: 22797712
[28] Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin Wound Healing: An Update on the Current Knowledge and Concepts. Eur Surg Res. 2017;58(1-2):81-94.
DOI: 10.1159/000454919 PMID: 27974711
[29] Lenselink EA. Role of fibronectin in normal wound healing. Int Wound J. 2015;12(3):313-6. DOI: 10.1111/iwj.12109
PMID: 23742140
[30] Dvorak AM. Mast cell-derived mediators of enhanced microvascular permeability, vascular permeability factor/vascular endothelial growth factor, histamine, and serotonin, cause leakage of macromolecules through a new endothelial cell permeability organelle, the vesiculo-vacuolar organelle. Chem Immunol Allergy. 2005;85:185-204.
DOI: 10.1159/000086517 PMID: 15970658
[31] Weller K, Foitzik K, Paus R, Syska W, Maurer M. Mast cells are required for normal healing of skin wounds in mice. FASEB J. 2006;20(13):2366-8. DOI: 10.1096/fj.06-5837fje
PMID: 16966487
[32] Zhao R, Liang H, Clarke E, Jackson C, Xue M. Inflammation in Chronic Wounds. Int J Mol Sci. 2016;17(12):2085.
DOI: 10.3390/ijms17122085 PMID: 27973441
[33] Bowers S, Franco E. Chronic Wounds: Evaluation and Management. Am Fam Physician. 2020;101(3):159-166.
PMID: 32003952
[34] Alhajj M, Goyal A. Physiology, Granulation Tissue. 2022. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. PMID: 32119289
[35] Jiang D, Scharffetter-Kochanek K. Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing. Front Cell Dev Biol. 2020;8:697. DOI: 10.3389/fcell.2020.00697
PMID: 32850818
[36] Goto T, Yanaga F, Ohtsuki I. Studies on the endothelin-1-induced contraction of rat granulation tissue pouch mediated by myofibroblasts. Biochim Biophys Acta. 1998;1405(1-3):55-66. DOI: 10.1016/s0167-4889(98)00105-0 PMID: 9784605
[37] Gu S, Dai H, Zhao X, Gui C, Gui J. AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling. Aging (Albany NY). 2020;12(8):6928-6946. DOI: 10.18632/aging.103051 PMID: 32291381
[38] Wang J, Wu H, Peng Y, Zhao Y, Qin Y, Zhang Y, et al. Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K/Akt pathways. J Nanobiotechnology. 2021;19(1):202. DOI: 10.1186/s12951-021-00942-0 PMID: 34233694
[39] Shaw TJ, Martin P. Wound repair: a showcase for cell plasticity and migration. Curr Opin Cell Biol. 2016;42:29-37.
DOI: 10.1016/j.ceb.2016.04.001 PMID: 27085790
[40] Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol. 2014;14(5):289-301. DOI: 10.1038/nri3646 PMID: 24722477
[41] Wager L, Leavesley D. MicroRNA regulation of epithelial-to-mesenchymal transition during re-epithelialisation: assessing an open wound. Wound Practice & Research: Journal of the Australian Wound Management Association. 2015;23(3):132-142. URL: https://journals.cambridgemedia.com.au/wpr/volume-23-number-3/microrna-regulation-epithelial-mesenchymal-transition-during-re-epithelialisation-assessing-open-wound
[42] Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007;25(1):9-18.
DOI: 10.1016/j.clindermatol.2006.09.007 PMID: 17276196
[43] Rousselle P, Braye F, Dayan G. Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2019;146:344-365.
DOI: 10.1016/j.addr.2018.06.019 PMID: 29981800
[44] Shi J, Ma X, Su Y, Song Y, Tian Y, Yuan S, et al. MiR-31 Mediates Inflammatory Signaling to Promote Re-Epithelialization during Skin Wound Healing. J Invest Dermatol. 2018;138(10):2253-2263. DOI: 10.1016/j.jid.2018.03.1521 PMID: 29605672
[45] Masson-Meyers DS, Andrade TAM, Caetano GF, Guimaraes FR, Leite MN, Leite SN, et al. Experimental models and methods for cutaneous wound healing assessment. Int J Exp Pathol. 2020;101(1-2):21-37. DOI: 10.1111/iep.12346 PMID: 32227524
[46] Díaz-Coránguez M, Liu X, Antonetti DA. Tight Junctions in Cell Proliferation. Int J Mol Sci. 2019;20(23):5972.
DOI: 10.3390/ijms20235972 PMID: 31783547
[47] Higashi T, Arnold TR, Stephenson RE, Dinshaw KM, Miller AL. Maintenance of the Epithelial Barrier and Remodeling of Cell-Cell Junctions during Cytokinesis. Curr Biol. 2016;26(14):1829-42. DOI: 10.1016/j.cub.2016.05.036 PMID: 27345163
[48] Witte MB, Barbul A. General principles of wound healing. Surg Clin North Am. 1997;77(3):509-28. DOI: 10.1016/s0039-6109(05)70566-1 PMID: 9194878
[49] Darby IA, Laverdet B, Bonté F, Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol. 2014;7:301-11. DOI: 10.2147/CCID.S50046 PMID: 25395868
[50] Ozsvar J, Yang C, Cain SA, Baldock C, Tarakanova A, Weiss AS. Tropoelastin and Elastin Assembly. Front Bioeng Biotechnol. 2021;9:643110. DOI: 10.3389/fbioe.2021.643110
PMID: 33718344
[51] Duca L, Floquet N, Alix AJ, Haye B, Debelle L. Elastin as a matrikine. Crit Rev Oncol Hematol. 2004;49(3):235-44.
DOI: 10.1016/j.critrevonc.2003.09.007 PMID: 15036263
[52] Almine JF, Wise SG, Weiss AS. Elastin signaling in wound repair. Birth Defects Res C Embryo Today. 2012;96(3):248-57. DOI: 10.1002/bdrc.21016 PMID: 23109320
[53] Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes. Front Physiol. 2018;9:419. DOI: 10.3389/fphys.2018.00419
PMID: 29765329
[54] Li B, Wang JH. Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J Tissue Viability. 2011;20(4):108-20. DOI: 10.1016/j.jtv.2009.11.004
PMID: 19995679
[55] Minor AJ, Coulombe KLK. Engineering a collagen matrix for cell-instructive regenerative angiogenesis. J Biomed Mater Res B Appl Biomater. 2020;108(6):2407-2416.
DOI: 10.1002/jbm.b.34573 PMID: 31984665
[56] Miekus N, Luise C, Sippl W, Baczek T, Schmelzer CEH, Heinz A. MMP-14 degrades tropoelastin and elastin. Biochimie. 2019;165:32-39. DOI: 10.1016/j.biochi.2019.07.001
PMID: 31278967
[57] Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012;25(7):304-14.
DOI: 10.1097/01.ASW.0000416006.55218.d0 PMID: 22713781
[58] Mathew-Steiner SS, Roy S, Sen CK. Collagen in Wound Healing. Bioengineering (Basel). 2021;8(5):63.
DOI: 10.3390/bioengineering8050063 PMID: 34064689
[59] Mofazzal Jahromi MA, Sahandi Zangabad P, Moosavi Basri SM, Sahandi Zangabad K, Ghamarypour A, Aref AR, et al. Nanomedicine and advanced technologies for burns: Preventing infection and facilitating wound healing. Adv Drug Deliv Rev. 2018;123:33-64. DOI: 10.1016/j.addr.2017.08.001
PMID: 28782570
[60] Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11:97.
DOI: 10.1186/1478-811X-11-97 PMID: 24359404
[61] Yang Y, Yuzawa S, Schlessinger J. Contacts between membrane proximal regions of the PDGF receptor ectodomain are required for receptor activation but not for receptor dimerization. Proc Natl Acad Sci U S A. 2008;105(22):7681-6.
DOI: 10.1073/pnas.0802896105 PMID: 18505839
[62] Yu J, Ustach C, Kim HR. Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 2003;36(1):49-59.
DOI: 10.5483/bmbrep.2003.36.1.049 PMID: 12542975
[63] Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A. Role of platelet-derived growth factor in wound healing. J Cell Biochem. 1991;45(4):319-26. DOI: 10.1002/jcb.240450403 PMID: 2045423
[64] Senzel L, Gnatenko DV, Bahou WF. The platelet proteome. Curr Opin Hematol. 2009;16(5):329-33.
DOI: 10.1097/MOH.0b013e32832e9dc6 PMID: 19550320
[65] Dalton CJ, Lemmon CA. Fibronectin: Molecular Structure, Fibrillar Structure and Mechanochemical Signaling. Cells. 2021;10(9):2443. DOI: 10.3390/cells10092443 PMID: 34572092
[66] To WS, Midwood KS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair. 2011;4:21. DOI: 10.1186/1755-1536-4-21
PMID: 21923916
[67] Singh P, Carraher C, Schwarzbauer JE. Assembly of fibronectin extracellular matrix. Annu Rev Cell Dev Biol. 2010;26:397-419. DOI: 10.1146/annurev-cellbio-100109-104020 PMID: 20690820
[68] Patten J, Wang K. Fibronectin in development and wound healing. Adv Drug Deliv Rev. 2021;170:353-368.
DOI: 10.1016/j.addr.2020.09.005 PMID: 32961203
[69] Wang Y, Reheman A, Spring CM, Kalantari J, Marshall AH, Wolberg AS, et al. Plasma fibronectin supports hemostasis and regulates thrombosis. J Clin Invest. 2014;124(10):4281-93.
DOI: 10.1172/JCI74630 PMID: 25180602
[70] Gale AJ. Continuing education course #2: current understanding of hemostasis. Toxicol Pathol. 2011;39(1):273-80.
DOI: 10.1177/0192623310389474 PMID: 21119054
[71] Trial J, Rossen RD, Rubio J, Knowlton AA. Inflammation and ischemia: macrophages activated by fibronectin fragments enhance the survival of injured cardiac myocytes. Exp Biol Med (Maywood). 2004;229(6):538-45.
DOI: 10.1177/153537020422900612 PMID: 15169973
[72] Speziale P, Arciola CR, Pietrocola G. Fibronectin and Its Role in Human Infective Diseases. Cells. 2019;8(12):1516.
DOI: 10.3390/cells8121516 PMID: 31779172
[73] Purohit T, Qin Z, Quan C, Lin Z, Quan T. Smad3-dependent CCN2 mediates fibronectin expression in human skin dermal fibroblasts. PLoS One. 2017;12(3):e0173191.
DOI: 10.1371/journal.pone.0173191 PMID: 28267785
[74] Shimizu M, Minakuchi K, Moon M, Koga J. Difference in interaction of fibronectin with type I collagen and type IV collagen. Biochim Biophys Acta. 1997;1339(1):53-61.
DOI: 10.1016/s0167-4838(96)00214-2 PMID: 9165099
[75] Kudo A, Kii I. Periostin function in communication with extracellular matrices. J Cell Commun Signal. 2018;12(1):301-308. DOI: 10.1007/s12079-017-0422-6 PMID: 29086200
[76] Calabro NE, Kristofik NJ, Kyriakides TR. Thrombospondin-2 and extracellular matrix assembly. Biochim Biophys Acta. 2014;1840(8):2396-402. DOI: 10.1016/j.bbagen.2014.01.013 PMID: 24440155
[77] Benito-Jardón M, Strohmeyer N, Ortega-Sanchís S, Bharadwaj M, Moser M, Müller DJ, et al. αv-Class integrin binding to fibronectin is solely mediated by RGD and unaffected by an RGE mutation. J Cell Biol. 2020;219(12):e202004198.
DOI: 10.1083/jcb.202004198 PMID: 33141174
[78] Bax DV, Rodgers UR, Bilek MM, Weiss AS. Cell adhesion to tropoelastin is mediated via the C-terminal GRKRK motif and integrin alphaVbeta3. J Biol Chem. 2009;284(42):28616-23. DOI: 10.1074/jbc.M109.017525 PMID: 19617625
[79] Ishihara J, Ishihara A, Fukunaga K, Sasaki K, White MJV, Briquez PS, et al. Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing. Nat Commun. 2018;9(1):2163. DOI: 10.1038/s41467-018-04525-w PMID: 29867149
[80] Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev. 2016;97:4-27. DOI: 10.1016/j.addr.2015.11.001 PMID: 26562801
[81] Couchman JR. Syndecans: proteoglycan regulators of cell-surface microdomains? Nat Rev Mol Cell Biol. 2003;4(12):926-37.
DOI: 10.1038/nrm1257 PMID: 14685171
[82] Cui C, Wang S, Myneni VD, Hitomi K, Kaartinen MT. Transglutaminase activity arising from Factor XIIIA is required for stabilization and conversion of plasma fibronectin into matrix in osteoblast cultures. Bone. 2014;59:127-38.
DOI: 10.1016/j.bone.2013.11.006 PMID: 24246248
[83] Bergmann S, von Buenau B, Vidal-Y-Sy S, Haftek M, Wladykowski E, Houdek P, et al. Claudin-1 decrease impacts epidermal barrier function in atopic dermatitis lesions dose-dependently. Sci Rep. 2020;10(1):2024. DOI: 10.1038/s41598-020-58718-9 PMID: 32029783
[84] Feldman GJ, Mullin JM, Ryan MP. Occludin: structure, function and regulation. Adv Drug Deliv Rev. 2005;57(6):883-917.
DOI: 10.1016/j.addr.2005.01.009 PMID: 15820558
[85] Cummins PM. Occludin: one protein, many forms. Mol Cell Biol. 2012;32(2):242-50. DOI: 10.1128/MCB.06029-11
PMID: 22083955
[86] González-Mariscal L, Betanzos A, Nava P, Jaramillo BE. Tight junction proteins. Prog Biophys Mol Biol. 2003;81(1):1-44.
DOI: 10.1016/s0079-6107(02)00037-8 PMID: 12475568
[87] National Center for Biotechnology Information. OCLN occludin [Homo sapiens (human)] Gene ID: 100506658. Updated 6-Jul-2025. URL: https://www.ncbi.nlm.nih.gov/gene/100506658
[88] Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141(7):1539-50. DOI: 10.1083/jcb.141.7.1539
PMID: 9647647
[89] Nishi H, Hashimoto K, Panchenko AR. Phosphorylation in protein-protein binding: effect on stability and function. Structure. 2011;19(12):1807-15. DOI: 10.1016/j.str.2011.09.021 PMID: 22153503
[90] Van Itallie CM, Anderson JM. Phosphorylation of tight junction transmembrane proteins: Many sites, much to do. Tissue Barriers. 2018;6(1):e1382671. DOI: 10.1080/21688370.2017.1382671 PMID: 29083946
[91] Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cβ phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61(6):1573-83. DOI: 10.2337/db11-1367
PMID: 22438576
[92] Shi J, Barakat M, Chen D, Chen L. Bicellular Tight Junctions and Wound Healing. Int J Mol Sci. 2018;19(12):3862.
DOI: 10.3390/ijms19123862 PMID: 30518037
[93] Tsukita S, Tanaka H, Tamura A. The Claudins: From Tight Junctions to Biological Systems. Trends Biochem Sci. 2019;44(2):141-152. DOI: 10.1016/j.tibs.2018.09.008
PMID: 30665499
[94] Bhat AA, Syed N, Therachiyil L, Nisar S, Hashem S, Macha MA, et al. Claudin-1, A Double-Edged Sword in Cancer. Int J Mol Sci. 2020;21(2):569. DOI: 10.3390/ijms21020569 PMID: 31952355
[95] National Center for Biotechnology Information. CLDN1 claudin 1 [Homo sapiens (human)] Gene ID: 9076. Updated 6-Jul-2025. URL: https://www.ncbi.nlm.nih.gov/gene/9076
[96] Hamazaki Y, Itoh M, Sasaki H, Furuse M, Tsukita S. Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. J Biol Chem. 2002;277(1):455-61.
DOI: 10.1074/jbc.M109005200 PMID: 11689568
[97] Gondelaud F, Ricard-Blum S. Structures and interactions of syndecans. FEBS J. 2019;286(15):2994-3007.
DOI: 10.1111/febs.14828 PMID: 30932318
[98] Shimada T, Yasuda S, Sugiura H, Yamagata K. Syntenin: PDZ Protein Regulating Signaling Pathways and Cellular Functions. Int J Mol Sci. 2019;20(17):4171. DOI: 10.3390/ijms20174171 PMID: 31454940
[99] Liu X, Shepherd TR, Murray AM, Xu Z, Fuentes EJ. The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics. Structure. 2013;21(3):342-54. DOI: 10.1016/j.str.2013.01.004 PMID: 23395182
[100] Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine. 2015;76(1):25-37. DOI: 10.1016/j.cyto.2015.06.017 PMID: 26185894
[101] Kwak A, Lee Y, Kim H, Kim S. Intracellular interleukin (IL)-1 family cytokine processing enzyme. Arch Pharm Res. 2016;39(11):1556-1564. DOI: 10.1007/s12272-016-0855-0 PMID: 27826753
[102] Xu D, Mu R, Wei X. The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis. Front Immunol. 2019;10:2025. DOI: 10.3389/fimmu.2019.02025
PMID: 31572353
[103] Momeni HR. Role of calpain in apoptosis. Cell J. 2011;13(2):65-72. PMID: 23507938
[104] Lefrançais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP, et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A. 2012;109(5):1673-8.
DOI: 10.1073/pnas.1115884109 PMID: 22307629
[105] Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407-20. DOI: 10.1038/nri.2016.58 PMID: 27291964
[106] Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-75. DOI: 10.1038/nri3399 PMID: 23435331
[107] Namikawa K, Okamoto T, Suzuki A, Konishi H, Kiyama H. Pancreatitis-associated protein-III is a novel macrophage chemoattractant implicated in nerve regeneration. J Neurosci. 2006;26(28):7460-7. DOI: 10.1523/JNEUROSCI.0023-06.2006 PMID: 16837594
[108] Kruger GM, Mosher JT, Bixby S, Joseph N, Iwashita T, Morrison SJ. Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron. 2002;35(4):657-69.
DOI: 10.1016/s0896-6273(02)00827-9 PMID: 12194866
[109] McCarty SM, Percival SL. Proteases and Delayed Wound Healing. Adv Wound Care (New Rochelle). 2013;2(8):438-447. DOI: 10.1089/wound.2012.0370 PMID: 24688830
[110] James GA, Swogger E, Wolcott R, Pulcini Ed, Secor P, Sestrich J, et al. Biofilms in chronic wounds. Wound Repair Regen. 2008;16(1):37-44. DOI: 10.1111/j.1524-475X.2007.00321.x PMID: 18086294
[111] Malinda KM, Kleinman HK. The laminins. Int J Biochem Cell Biol. 1996;28(9):957-9. DOI: 10.1016/1357-2725(96)00042-8 PMID: 8930117
[112] Mukherjee C, Saleem S, DAS S, Biswas SC, Bhattacharyya D. Human placental laminin: Role in neuronal differentiation, cell adhesion and proliferation. J Biosci. 2020;45:93.
PMID: 32713856
[113] Min SK, Lee SC, Hong SD, Chung CP, Park WH, Min BM. The effect of a laminin-5-derived peptide coated onto chitin microfibers on re-epithelialization in early-stage wound healing. Biomaterials. 2010;31(17):4725-30.
DOI: 10.1016/j.biomaterials.2010.02.045 PMID: 20303583
[114] Zhu Y, Cankova Z, Iwanaszko M, Lichtor S, Mrksich M, Ameer GA. Potent laminin-inspired antioxidant regenerative dressing accelerates wound healing in diabetes. Proc Natl Acad Sci U S A. 2018;115(26):6816-6821.
DOI: 10.1073/pnas.1804262115 PMID: 29891655
[115] Malinda KM, Wysocki AB, Koblinski JE, Kleinman HK, Ponce ML. Angiogenic laminin-derived peptides stimulate wound healing. Int J Biochem Cell Biol. 2008;40(12):2771-80.
DOI: 10.1016/j.biocel.2008.05.025 PMID: 18603014
[116] Longmate WM, Lyons SP, DeFreest L, Van De Water L, DiPersio CM. Opposing Roles of Epidermal Integrins α3β1 and α9β1 in Regulation of mTLD/BMP-1-Mediated Laminin-γ2 Processing during Wound Healing. J Invest Dermatol. 2018;138(2):444-451. DOI: 10.1016/j.jid.2017.09.004
PMID: 28923241
[117] Chang YC, Wang JD, Chang HY, Zhou P, Hahn RA, Gordon MK, et al. Expression of Laminin γ2 Proteolytic Fragments in Murine Skin Following Exposure to Sulfur Mustard. Anat Rec (Hoboken). 2020;303(6):1642-1652.
DOI: 10.1002/ar.24405 PMID: 32421930
[118] Michopoulou A, Montmasson M, Garnier C, Lambert E, Dayan G, Rousselle P. A novel mechanism in wound healing: Laminin 332 drives MMP9/14 activity by recruiting syndecan-1 and CD44. Matrix Biol. 2020;94:1-17.
DOI: 10.1016/j.matbio.2020.06.004 PMID: 32621878
[119] Mithieux SM, Weiss AS. Elastin. Adv Protein Chem. 2005;70:437-61. DOI: 10.1016/S0065-3233(05)70013-9
PMID: 15837523
[120] Heinz A, Schräder CU, Baud S, Keeley FW, Mithieux SM, Weiss AS, et al. Molecular-level characterization of elastin-like constructs and human aortic elastin. Matrix Biol. 2014;38:12-21. DOI: 10.1016/j.matbio.2014.07.006 PMID: 25068896
[121] Antonicelli F, Bellon G, Debelle L, Hornebeck W. Elastin-elastases and inflamm-aging. Curr Top Dev Biol. 2007;79:99-155. DOI: 10.1016/S0070-2153(06)79005-6 PMID: 17498549
[122] Almeida-González FR, González-Vázquez A, Mithieux SM, O'Brien FJ, Weiss AS, Brougham CM. A step closer to elastogenesis on demand; Inducing mature elastic fibre deposition in a natural biomaterial scaffold. Mater Sci Eng C Mater Biol Appl. 2021;120:111788. DOI: 10.1016/j.msec.2020.111788 PMID: 33545914
[123] Wang K, Meng X, Guo Z. Elastin Structure, Synthesis, Regulatory Mechanism and Relationship With Cardiovascular Diseases. Front Cell Dev Biol. 2021;9:596702.
DOI: 10.3389/fcell.2021.596702 PMID: 34917605
[124] Rodgers UR, Weiss AS. Cellular interactions with elastin. Pathol Biol (Paris). 2005;53(7):390-8.
DOI: 10.1016/j.patbio.2004.12.022 PMID: 16085115
[125] de Castro Brás LE, Frangogiannis NG. Extracellular matrix-derived peptides in tissue remodeling and fibrosis. Matrix Biol. 2020;91-92:176-187. DOI: 10.1016/j.matbio.2020.04.006
PMID: 32438055
[126] Wahart A, Hocine T, Albrecht C, Henry A, Sarazin T, Martiny L, et al. Role of elastin peptides and elastin receptor complex in metabolic and cardiovascular diseases. FEBS J. 2019;286(15):2980-2993. DOI: 10.1111/febs.14836
PMID: 30946528
[127] Scandolera A, Odoul L, Salesse S, Guillot A, Blaise S, Kawecki C, et al. The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti-tumoral Potential. Front Pharmacol. 2016;7:32. DOI: 10.3389/fphar.2016.00032
PMID: 26973522
[128] P01127 PDGFB_HUMAN [Homo sapiens (human)] Gene ID: PDGFB. Updated 6-Jul-2025.
URL: https://www.uniprot.org/uniprotkb/P01127/entry
[129] PDGF binds to extracellular matrix proteins [Homo sapiens (human)] ID: R-HSA-382054.2. Updated 6-Jul-2025.
URL: https://reactome.org/PathwayBrowser/#/R-HSA-186797&SEL=R-HSA-382054&PATH=R-HSA-162582,R-HSA-9006934
[130] Gao AG, Lindberg FP, Finn MB, Blystone SD, Brown EJ, Frazier WA. Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin. J Biol Chem. 1996;271(1):21-4. DOI: 10.1074/jbc.271.1.21 PMID: 8550562
[131] Kuznetsova SA, Mahoney DJ, Martin-Manso G, Ali T, Nentwich HA, Sipes JM, et al. TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly. Matrix Biol. 2008;27(3):201-10.
DOI: 10.1016/j.matbio.2007.10.003 PMID: 18042364
[132] EBI-2566729 OR EBI-11789924. Updated 6-Jul-2025.
[133] Takino T, Sato H, Shinagawa A, Seiki M. Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family. J Biol Chem. 1995;270(39):23013-20. DOI: 10.1074/jbc.270.39.23013
PMID: 7559440
[134] VEGF-A,C,D bind to VEGFR2 leading to receptor dimerization [Homo sapiens (human)] ID: R-HSA-194310.3. Reactome. Updated 2025 Jul 6.
[135] Khayati F, Pérez-Cano L, Maouche K, Sadoux A, Boutalbi Z, Podgorniak MP, et al. EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF. Oncotarget. 2015;6(12):9766-80. DOI: 10.18632/oncotarget.2870
PMID: 25825981
[136] Sang QA, Bodden MK, Windsor LJ. Activation of human progelatinase A by collagenase and matrilysin: activation of procollagenase by matrilysin. J Protein Chem. 1996;15(3):243-53. DOI: 10.1007/BF01887112 PMID: 8804571
[137] Morrison CJ, Butler GS, Bigg HF, Roberts CR, Soloway PD, Overall CM. Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway. J Biol Chem. 2001;276(50):47402-10. DOI: 10.1074/jbc.M108643200 PMID: 11584019
[138] Schnapp LM, Hatch N, Ramos DM, Klimanskaya IV, Sheppard D, Pytela R. The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. J Biol Chem. 1995;270(39):23196-202.
DOI: 10.1074/jbc.270.39.23196 PMID: 7559467
[139] PDGFA. GeneMania. Updated 2025 Jul 6.
URL: https://genemania.org/search/homo-sapiens/PDGFA/
[140] HGF(495-728) [extracellular region] [Homo sapiens (human)] Stable Identifier: R-HSA-141767. Reactome. Updated 2025 Jul 6. URL: https://reactome.org/content/detail/R-HSA-141767
[141] McElroy CA, Dohm JA, Walsh ST. Structural and biophysical studies of the human IL-7/IL-7Ralpha complex. Structure. 2009;17(1):54-65. DOI: 10.1016/j.str.2008.10.019
PMID: 19141282
[142] Futosi K, Fodor S, Mócsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol. 2013;17(3):638-50.
DOI: 10.1016/j.intimp.2013.06.034 PMID: 23994464
[143] STRING [Internet]. [cited 2022 Jul 1]. URL: https://string-db.org/cgi/network?taskId=bOa9HNe68ZGz&sessionId=bwZkM5lzLdhc.
[144] cldn5, cldn1, cldn2, cldn3. GeneMania. Updated 2025 Jul 6. URL: https://genemania.org/search/homo-sapiens/cldn5/cldn1/cldn2/cldn3/
[145] Crabbe T, O'Connell JP, Smith BJ, Docherty AJ. Reciprocated matrix metalloproteinase activation: a process performed by interstitial collagenase and progelatinase A. Biochemistry. 1994;33(48):14419-25.
DOI: 10.1021/bi00252a007 PMID: 7981201
[146] Strongin AY, Marmer BL, Grant GA, Goldberg GI. Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2. J Biol Chem. 1993;268(19):14033-9. PMID: 8314771
[147] Nishida Y, Miyamori H, Thompson EW, Takino T, Endo Y, Sato H. Activation of matrix metalloproteinase-2 (MMP-2) by membrane type 1 matrix metalloproteinase through an artificial receptor for proMMP-2 generates active MMP-2. Cancer Res. 2008;68(21):9096-104. DOI: 10.1158/0008-5472.CAN-08-2522 PMID: 18974156
[148] Tam EM, Wu YI, Butler GS, Stack MS, Overall CM. Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1-MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1-MMP inhibits cell invasion by disrupting native type I collagen cleavage. J Biol Chem. 2002;277(41):39005-14.
DOI: 10.1074/jbc.M206874200 PMID: 12145314
[149] Steffensen B, Bigg HF, Overall CM. The involvement of the fibronectin type II-like modules of human gelatinase A in cell surface localization and activation. J Biol Chem. 1998;273(32):20622-8. DOI: 10.1074/jbc.273.32.20622
PMID: 9685420
[150] Latifi-Navid H, Soheili ZS, Samiei S, Sadeghi M, Taghizadeh S, Pirmardan ER, et al. Network analysis and the impact of Aflibercept on specific mediators of angiogenesis in HUVEC cells. J Cell Mol Med. 2021;25(17):8285-8299.
DOI: 10.1111/jcmm.16778 PMID: 34250732
[151] Turner CT, Zeglinski MR, Richardson KC, Zhao H, Shen Y, Papp A, et al. Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling. J Invest Dermatol. 2019;139(4):930-939.
DOI: 10.1016/j.jid.2018.09.031 PMID: 30395844