نوع مقاله : مروری

نویسندگان

1 دانشیار گروه سلول‌های بنیادی و پزشکی بازساختی، پژوهشکده بیوتکنولوژی پزشکی، پژوهشگاه ملی مهندسی ژنتیک و زیست‌فناوری، تهران، ایران

2 استادیار گروه سلول‌های بنیادی و پزشکی بازساختی، پژوهشکده بیوتکنولوژی پزشکی، پژوهشگاه ملی مهندسی ژنتیک و زیست‌فناوری، تهران، ایران

چکیده

زمینه و هدف  سلول‌های بنیادی مزانشیمی (MSCها) به‌عنوان یک منبع جذاب برای سلول‌درمانی بافت‌های آسیب‌دیده شناخته شده‌اند. توانایی تمایز چندگانه، دستیابی آسان، ایمنی‌زایی پایین و نقش چشمگیر در فیزیولوژی ترمیم زخم باعث استفاده گسترده از این سلول‌ها در ترمیم زخم شده است. در این مطالعه مروری، نقش MSCها در ترمیم زخم‌های پوستی مورد بحث قرار می‌گیرد.
مواد و روش‌ها این مقاله مروری براساس یافته‌های حاصل از جستجوی پایگاه داده‌های PubMed و Google Scholar بین سال‌های 1990 تا 2020 و سایت اینترنتی ClinicalTrials.gov تهیه شد.
یافته‌ها: MSCها در تمام مراحل ترمیم زخم موثرند. این سلول‌ها به جایگاه آسیب پوستی مهاجرت می ‌کنند و علاوه بر تمایز به سلول‌های پوستی، از طریق پیام‌رسانی پاراکرین، پاسخ‌های ایمنی و التهابی را مهار و تکثیر و تمایز سلول‌های پیسشاز ساکن در محل را تحریک می‌کنند و به رگزایی، تشکیل مجدد اپیتلیوم و شکل‌گیری بافت گرانوله منجر می‌شوند. در مرحله بازسازی و بلوغ نیز این سلول‌ها تشکیل بافت فیبروز و انقباض زخم را کاهش و بیان کلاژن و مقاومت کششی زخم را افزایش می‌دهند. این سلول‌ها عملکرد خود را براساس ویژگی‌های مولکولی محل ضایعه تغییر می‌دهند و باعث ایجاد ریزمحیط ترمیم‌کننده زخم به جای ریزمحیط فیبروتیک می‌شوند.  
نتیجه‌گیری: امروزه پیشرفت‌های شگرفی در روش‌های تحویل MSCها به زخم‌های در حال ترمیم حاصل شده است. این سلول‌ها با تزریق داخل وریدی یا داخل درمی، همراه با داربست‌ها، به شکل اسپری پلیمر فیبرین یا همراه با هیدروژل‌ها استفاده می‌شوند. علاوه بر این، وزیکول‌های خارج سلولی و محیط هم‌افزایی شده این سلول‌ها به‌تنهایی نیز مؤثر است. مطالعات آینده می‌تواند به راهکارهای درمانی مؤثرتری در زمینه استفاده از MSCها در ترمیم زخم منتهی شود.
 

کلیدواژه‌ها

عنوان مقاله [English]

The importance of mesenchymal stem cells in skin wound healing

نویسندگان [English]

  • Masoumeh Fakhr Taha 1
  • Arash Javeri 2

1 Associate professor, Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran .

2 Assistant professor, Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

چکیده [English]

Introduction: Mesenchymal stem cells (MSCs) have been identified as an attractive source for cell therapy of damaged tissues. The multipotential differentiation capability, easy accessibility, low immunogenicity and significant role in wound healing physiology have led to the widespread use of these cells for wound healing. In this review study, the role of mesenchymal stem cells in repair of skin wounds is discussed . Materials and Methods: This review was written based on findings from a search of the PubMed and Google Scholar databases between 1990 and 2020. Results: Mesenchymal stem cells have important roles at all stages of wound healing. These cells migrate to the site of skin damage and not only differentiate into the skin cells but also through paracrine signalling inhibit the immune and inflammatory responses, induce proliferation and differentiation of resident progenitor cells and result in angiogenesis, epithelialization and granule tissue formation. In the regeneration and maturation phase, the MSCs reduce scar formation and wound contraction and increase collagen expression and wound tensile strength. These cells alter their function based on the biomolecular properties of the lesion site, and create a wound-healing rather than fibrotic microenvironment .
Conclusion: Todays, significant advances have been made in the delivery of MSCs into healing wounds. These cells are delivered via intravenous or intradermal injection, or delivered with scaffolds, as a fibrin polymer spray or with hydrogels. In addition, the extracellular vesicles and conditioned medium of MSCs alone are effective. Future studies could lead to more effective strategies for the use of mesenchymal stem cells in wound healing .
Received

کلیدواژه‌ها [English]

  • Mesenchymal stem cells
  • Paracrine
  • Immunomodulation
  • Healing
  • Skin wound
[1]. Faghih H, Javeri A, Taha MF. Impact of early subcultures on stemness, migration and angiogenic potential of adipose tissue-derived stem cells and their resistance to in vitro ischemic condition. Cytotechnology. 2017;69(6):885900.
[2]. Nakagami H, Morishita R, Maeda K, Kikuchi Y, Ogihara T, Kaneda Y. Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. Journal of atherosclerosis and thrombosis. 2006;13(2):77-81.
[3]. Taha MF, Javeri A, Rohban S, Mowla SJ. Upregulation of pluripotency markers in adipose tissue-derived stem cells by miR-302 and leukemia inhibitory factor. BioMed research international. 2014;2014:941486.
[4]. Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Bioscience reports. 2015;35(2):e00191.
[5]. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7.
[6]. Kupcova Skalnikova H. Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie. 2013;95(12):2196-211.
[7]. Andrzejewska A, Lukomska B, Janowski M. Concise Review: Mesenchymal Stem Cells: From Roots to Boost. Stem cells. 2019;37(7):855-64.
[8]. Tu Z, Li Q, Bu H, Lin F. Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem cells and development. 2010;19(11):1803-9.
[9]. Moll G, Jitschin R, von Bahr L, Rasmusson-Duprez I, Sundberg B, Lonnies L, et al. Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses. PloS one. 2011;6(7):e21703.
[10]. Munir H, Rainger GE, Nash GB, McGettrick H. Analyzing the effects of stromal cells on the recruitment of leukocytes from flow. Journal of visualized experiments : JoVE. 2015(95):e52480.
[11]. Brandau S, Jakob M, Bruderek K, Bootz F, Giebel B, Radtke S, et al. Mesenchymal stem cells augment the anti-bacterial activity of neutrophil granulocytes. PloS one. 2014;9(9):e106903.
[12]. Brown JM, Nemeth K, Kushnir-Sukhov NM, Metcalfe DD, Mezey E. Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2011;41(4):526-34.
[13]. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327-33.
[14]. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. Journal of immunology. 2006;177(4):2080-7.
[15]. Su WR, Zhang QZ, Shi SH, Nguyen AL, Le AD. Human gingiva-derived mesenchymal stromal cells attenuate contact hypersensitivity via prostaglandin E2-dependent mechanisms. Stem cells. 2011;29(11):1849-60.
[16]. Chen PM, Liu KJ, Hsu PJ, Wei CF, Bai CH, Ho LJ, et al. Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. Journal of leukocyte biology. 2014;96(2):295-303.
[17]. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105(7):2821-7.
[18]. Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versushost disease. Stem cells. 2006;24(11):2582-91.
[19]. Ghannam S, Pene J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. Journal of immunology. 2010;185(1):302-12.
[20]. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-72.
[21]. Zhang J, Huang X, Wang H, Liu X, Zhang T, Wang Y, et al. The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem cell research & therapy. 2015;6:234.
[22]. Ullah M, Liu DD, Thakor AS. Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience. 2019;15:421-38.
[23]. Saeedi P, Halabian R, Imani Fooladi AA. A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies. Stem cell investigation. 2019;6:34.
[24]. Mezey E, Nemeth K. Mesenchymal stem cells and infectious diseases: Smarter than drugs. Immunology letters. 2015;168(2):208-14.
[25]. Meisel R, Brockers S, Heseler K, Degistirici O, Bulle H, Woite C, et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia. 2011;25(4):648-54.
[26]. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. International journal of molecular sciences. 2017;18(9):1852.
[27]. Attar-Schneider O, Zismanov V, Drucker L, Gottfried M. Secretome of human bone marrow mesenchymal stem cells: an emerging player in lung cancer progression and mechanisms of translation initiation. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2016;37(4):4755-65.
[28]. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449(7162):557-63.
[29]. Koniusz S, Andrzejewska A, Muraca M, Srivastava AK, Janowski M, Lukomska B. Extracellular Vesicles in Physiology, Pathology, and Therapy of the Immune and Central Nervous System, with Focus on Extracellular Vesicles Derived from Mesenchymal Stem Cells as Therapeutic Tools. Frontiers in cellular neuroscience. 2016;10:109.
[30]. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications. Frontiers in cell and developmental biology. 2020;8:149.
[31]. Mustoe TA, O'Shaughnessy K, Kloeters O. Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plastic and reconstructive surgery. 2006;117(7 Suppl):35S-41S.
[32]. Cha J, Falanga V. Stem cells in cutaneous wound healing. Clinics in dermatology. 2007;25(1):73-8. [33]. Vande Berg JS, Rudolph R, Hollan C, Haywood-Reid PL. Fibroblast senescence in pressure ulcers. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 1998;6(1):38-49.
[34]. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, et al. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem cells. 2004;22(5):812-22.
[35]. Chen JS, Wong VW, Gurtner GC. Therapeutic potential of bone marrow-derived mesenchymal stem cells for cutaneous wound healing. Frontiers in immunology. 2012;3:192.
[36]. Schmidt BA, Horsley V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development. 2013;140(7):1517-27.
[37]. Al‐Shaibani MBH WX, Lovat PE, Dickinson AM. Cellular Therapy for Wounds: Applications of Mesenchymal Stem Cells in Wound Healing,. Wound Healing - New insights into Ancient Challenges2016. p. 99-131.
[38]. Li P, Gong Z, Shultz LD, Ren G. Mesenchymal stem cells: From regeneration to cancer. Pharmacology & therapeutics. 2019;200:42-54.
[39]. Duscher D, Barrera J, Wong VW, Maan ZN, Whittam AJ, Januszyk M, et al. Stem Cells in Wound Healing: The Future of Regenerative Medicine? A Mini-Review. Gerontology. 2016;62(2):216-25.
[40]. Argolo Neto NM, Del Carlo RJ, Monteiro BS, Nardi NB, Chagastelles PC, de Brito AF, et al. Role of autologous mesenchymal stem cells associated with platelet-rich plasma on healing of cutaneous wounds in diabetic mice. Clinical and experimental dermatology. 2012;37(5):544-53.
[41]. McFarlin K, Gao X, Liu YB, Dulchavsky DS, Kwon D, Arbab AS, et al. Bone marrow-derived mesenchymal stromal cells accelerate wound healing in the rat. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 2006;14(4):471-8. [42]. Rustad KC, Gurtner GC. Mesenchymal Stem Cells Home to Sites of Injury and Inflammation. Advances in wound care. 2012;1(4):147-52.
[43]. Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, et al. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European heart journal. 2006;27(9):1114-22.
[44]. Angelos MG, Kutala VK, Torres CA, He G, Stoner JD, Mohammad M, et al. Hypoxic reperfusion of the ischemic heart and oxygen radical generation. American journal of physiology Heart and circulatory physiology. 2006;290(1):H341-7.
[45]. Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue engineering. 2007;13(6):1299-312.
[46]. Izi L RLR, Mahdavi shahri N, Rejhan Nejad M, Birjandi Nejad A. Preparation of human 3D skin matrix and investigation of the interaction between rat adherent bone marrow cells and prepared matrix. j Sabzevar university Med Sci. 2016;23(2): 241-52.
[47]. Hu MS, Borrelli MR, Lorenz HP, Longaker MT, Wan DC. Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential. Stem cells international. 2018;2018:6901983.
[48]. Wong VW, Rustad KC, Galvez MG, Neofytou E, Glotzbach JP, Januszyk M, et al. Engineered pullulan-collagen composite dermal hydrogels improve early cutaneous wound healing. Tissue engineering Part A. 2011;17(56):631-44.
[49]. Rustad KC, Wong VW, Sorkin M, Glotzbach JP, Major MR, Rajadas J, et al. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials. 2012;33(1):80-90.
[50]. Wong VW, Rustad KC, Glotzbach JP, Sorkin M, Inayathullah M, Major MR, et al. Pullulan hydrogels improve mesenchymal stem cell delivery into highoxidative-stress wounds. Macromolecular bioscience. 2011;11(11):1458-66.
[51]. Xu K, Cantu DA, Fu Y, Kim J, Zheng X, Hematti P, et al. Thiol-ene Michael-type formation of gelatin/poly(ethylene glycol) biomatrices for threedimensional mesenchymal stromal/stem cell administration to cutaneous wounds. Acta biomaterialia. 2013;9(11):8802-14.
[52]. Garzon I, Miyake J, Gonzalez-Andrades M, Carmona R, Carda C, Sanchez-Quevedo Mdel C, et al. Wharton's jelly stem cells: a novel cell source for oral mucosa and skin epithelia regeneration. Stem cells translational medicine. 2013;2(8):625-32.
[53]. Baer PC, Doring C, Hansmann ML, Schubert R, Geiger H. New insights into epithelial differentiation of human adipose-derived stem cells. Journal of tissue engineering and regenerative medicine. 2013;7(4):271-8.
[54]. Dogan A, Demirci S, Sahin F. In vitro differentiation of human tooth germ stem cells into endothelial- and epithelial-like cells. Cell biology international. 2015;39(1):94-103.
[55]. Chun-mao H, Su-yi W, Ping-ping L, Hang-hui C. Human bone marrow-derived mesenchymal stem cells differentiate into epidermal-like cells in vitro. Differentiation; research in biological diversity. 2007;75(4):292-8.
[56]. Llames SG, Del Rio M, Larcher F, Garcia E, Garcia M, Escamez MJ, et al. Human plasma as a dermal scaffold for the generation of a completely autologous bioengineered skin. Transplantation. 2004;77(3):350-5.
[57]. Javeri A, Lyons JG, Huang XX, Halliday GM. Downregulation of Cockayne syndrome B protein reduces human 8-oxoguanine DNA glycosylase-1 expression and repair of UV radiation-induced 8-oxo-7,8-dihydro-2'deoxyguanine. Cancer science. 2011;102(9):1651-8.
[58]. Smola H, Thiekotter G, Fusenig NE. Mutual induction of growth factor gene expression by epidermal-dermal cell interaction. The Journal of cell biology. 1993;122(2):417-29.
[59]. Boyce ST, Warden GD. Principles and practices for treatment of cutaneous wounds with cultured skin substitutes. American journal of surgery. 2002;183(4):44556.
[60]. Javeri A, Huang XX, Bernerd F, Mason RS, Halliday GM. Human 8-oxoguanine-DNA glycosylase 1 protein and gene are expressed more abundantly in the superficial than basal layer of human epidermis. DNA repair. 2008;7(9):1542-50.
[61]. Wha Kim S, Lee IW, Cho HJ, Cho KH, Han Kim K, Chung JH, et al. Fibroblasts and ascorbate regulate epidermalization in reconstructed human epidermis. Journal of dermatological science. 2002;30(3):215-23.
[62]. Kraft R, Herndon DN, Al-Mousawi AM, Williams FN, Finnerty CC, Jeschke MG. Burn size and survival probability in paediatric patients in modern burn care: a prospective observational cohort study. Lancet. 2012 Mar 17;379(9820):1013-21.
[63]. Laverdet B, Micallef L, Lebreton C, Mollard J, Lataillade JJ, Coulomb B, et al. Use of mesenchymal stem cells for cutaneous repair and skin substitute elaboration. Pathologie-biologie. 2014;62(2):108-17. [64]. Martin-Piedra MA, Alfonso-Rodriguez CA, Zapater A, Durand-Herrera D, Chato-Astrain J, Campos F, et al. Effective use of mesenchymal stem cells in human skin substitutes generated by tissue engineering. European cells & materials. 2019;37:233-49.