Current Stem Cell Research & TherapyCurrent Stem Cell Research & TherapyCurrent Stem Cell Research & Therapy1574-888X2212-3946Bentham Science64576010.2174/1574888X18666230418121053MedicineResearch ArticleThe Current Status and Future Direction of Extracellular Nano-vesicles in the Alleviation of Skin DisordersGhorbaniRaziyehinfo@benthamscience.netHosseinzadehSimzarinfo@benthamscience.netAzariArezoinfo@benthamscience.netTaghipourNiloofarinfo@benthamscience.netSoleimaniMasoudinfo@benthamscience.netRahimpourAzaminfo@benthamscience.netAbbaszadehHojjatinfo@benthamscience.netDepartment of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical SciencesDepartment of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine,, Shahid Beheshti University of Medical SciencesLaser Application in Medical Sciences Research Center,, Shahid Beheshti University of Medical Sciences0103202419335136611012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1574-888X/article/view/645760

Exosomes are extracellular vesicles (EVs) that originate from endocytic membranes. The transfer of biomolecules and biological compounds such as enzymes, proteins, RNA, lipids, and cellular waste disposal through exosomes plays an essential function in cell-cell communication and regulation of pathological and physiological processes in skin disease. The skin is one of the vital organs that makes up about 8% of the total body mass. This organ consists of three layers, epidermis, dermis, and hypodermis that cover the outer surface of the body. Heterogeneity and endogeneity of exosomes is an advantage that distinguishes them from nanoparticles and liposomes and leads to their widespread usage in the remedy of dermal diseases. The biocompatible nature of these extracellular vesicles has attracted the attention of many health researchers. In this review article, we will first discuss the biogenesis of exosomes, their contents, separation methods, and the advantages and disadvantages of exosomes. Then we will highlight recent developments related to the therapeutic applications of exosomes in the treatment of common skin disorders like atopic dermatitis, alopecia, epidermolysis bullosa, keloid, melanoma, psoriasis, and systemic sclerosis.

Cell-free therapyextracellular vesiclesESCRT pathwaytherapeutic nanovesiclesnegative zeta potentialmelanocytes.Montagna W. The structure and function of skin. (3rd ed.), AmsterdamElsevier 2012.Halata Z, Grim M, Baumann KI. Current understanding of Merkel cells, touch reception and the skin. Expert Rev Dermatol 2010; 5(1): 109-16. doi: 10.1586/edm.09.70Tsatmali M, Ancans J, Thody AJ. Melanocyte function and its control by melanocortin peptides. J Histochem Cytochem 2002; 50(2): 125-33. doi: 10.1177/002215540205000201 PMID: 11799132Clayton K, Vallejo AF, Davies J, Sirvent S, Polak ME. Langerhans cells—programmed by the epidermis. Front Immunol 2017; 8: 1676. doi: 10.3389/fimmu.2017.01676 PMID: 29238347Benson HA, Watkinson AC. Topical and transdermal drug delivery: principles and practice. Hoboken, New Jersey John Wiley & Sons 2012.Gupta RK. Adipocytes. Curr Biol 2014; 24(20): R988-93. doi: 10.1016/j.cub.2014.09.003 PMID: 25442852Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res 2012; 49(1): 35-43. doi: 10.1159/000339613 PMID: 22797712Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin wound healing: An update on the current knowledge and concepts. s. Eur Surg Res 2017; 58(1-2): 81-94. doi: 10.1159/000454919 PMID: 27974711Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987; 262(19): 9412-20. doi: 10.1016/S0021-9258(18)48095-7 PMID: 3597417Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 2014; 29: 116-25. doi: 10.1016/j.ceb.2014.05.004 PMID: 24959705Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cellderived extracellular vesicles: Toward cell-free therapeutic applications. Mol Ther 2015; 23(5): 812-23. doi: 10.1038/mt.2015.44 PMID: 25868399Lindenbergh MFS, Wubbolts R, Borg EGF. ’T Veld EM, Boes M, Stoorvogel W. Dendritic cells release exosomes together with phagocytosed pathogen; potential implications for the role of exosomes in antigen presentation. J Extracell Vesicles 2020; 9(1): 1798606. doi: 10.1080/20013078.2020.1798606 PMID: 32944186Manchon E, Hirt N, Bouaziz JD, Jabrane-Ferrat N, Al-Daccak R. Stem cells-derived extracellular vesicles: Potential therapeutics for wound healing in chronic inflammatory skin diseases. Int J Mol Sci 2021; 22(6): 3130. doi: 10.3390/ijms22063130 PMID: 33808520Samanta S, Rajasingh S, Drosos N, Zhou Z, Dawn B, Rajasingh J. Exosomes: New molecular targets of diseases. Acta Pharmacol Sin 2018; 39(4): 501-13. doi: 10.1038/aps.2017.162 PMID: 29219950Gonda A, Kabagwira J, Senthil GN, Wall NR. Internalization of exosomes through receptor-mediated endocytosis. Mol Cancer Res 2019; 17(2): 337-47. doi: 10.1158/1541-7786.MCR-18-0891 PMID: 30487244Harischandra DS, Ghaisas S, Rokad D, Kanthasamy AG. Exosomes in toxicology: Relevance to chemical exposure and pathogenesis of environmentally linked diseases. Toxicol Sci 2017; 158(1): 3-13. doi: 10.1093/toxsci/kfx074 PMID: 28505322Rajendran L, Honsho M, Zahn TR, et al. Alzheimer’s disease βamyloid peptides are released in association with exosomes. Proc Natl Acad Sci 2006; 103(30): 11172-7. doi: 10.1073/pnas.0603838103 PMID: 16837572Hoshino A, Costa-Silva B, Shen TL, et al. Tumour exosome integrins determine organotropic metastasis. Nature 2015; 527(7578): 329-35. doi: 10.1038/nature15756 PMID: 26524530Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Badiavas EV. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev 2015; 24(14): 1635-47. doi: 10.1089/scd.2014.0316 PMID: 25867197Ferreira AF, Cunha PS, Carregal VM, et al. Extracellular vesicles from adipose-derived mesenchymal stem/stromal cells accelerate migration and activate AKT pathway in human keratinocytes and fibroblasts independently of miR-205 activity. Stem Cells Int 2017; 2017: 1-14. doi: 10.1155/2017/9841035 PMID: 29358958Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 1983; 97(2): 329-39. doi: 10.1083/jcb.97.2.329 PMID: 6309857Batista BS, Eng WS, Pilobello KT, Hendricks-Muñoz KD, Mahal LK. Identification of a conserved glycan signature for microvesicles. J Proteome Res 2011; 10(10): 4624-33. doi: 10.1021/pr200434y PMID: 21859146Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: Exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol 2015; 40: 41-51. doi: 10.1016/j.semcdb.2015.02.010Sahu R, Kaushik S, Clement CC, et al. Microautophagy of cytosolic proteins by late endosomes. Dev Cell 2011; 20(1): 131-9. doi: 10.1016/j.devcel.2010.12.003 PMID: 21238931Record M. Intercellular communication by exosomes in placenta: A possible role in cell fusion? Placenta 2014; 35(5): 297-302. doi: 10.1016/j.placenta.2014.02.009 PMID: 24661568Henne WM, Buchkovich NJ, Emr SD. The ESCRT pathway. Dev Cell 2011; 21(1): 77-91. doi: 10.1016/j.devcel.2011.05.015 PMID: 21763610Henne WM, Stenmark H, Emr SD. Molecular mechanisms of the membrane sculpting ESCRT pathway. Cold Spring Harb Perspect Biol 2013; 5(9): a016766. doi: 10.1101/cshperspect.a016766 PMID: 24003212Juan T, Fürthauer M. Biogenesis and function of ESCRTdependent extracellular vesicles. Semin Cell Dev Biol 2018; 74: 66-77. doi: 10.1016/j.semcdb.2017.08.022Tschuschke M, Kocherova I, Bryja A, et al. Inclusion biogenesis, methods of isolation and clinical application of human cellular exosomes. J Clin Med 2020; 9(2): 436. doi: 10.3390/jcm9020436 PMID: 32041096Conde-Vancells J, Rodriguez-Suarez E, Embade N, et al. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res 2008; 7(12): 5157-66. doi: 10.1021/pr8004887 PMID: 19367702Subra C, Grand D, Laulagnier K, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res 2010; 51(8): 2105-20. doi: 10.1194/jlr.M003657 PMID: 20424270Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29(4): 341-5. doi: 10.1038/nbt.1807 PMID: 21423189Théry C, Boussac M, Véron P, et al. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 2001; 166(12): 7309-18. doi: 10.4049/jimmunol.166.12.7309 PMID: 11390481Kalra H, Simpson RJ, Ji H, et al. Vesiclepedia: A compendium for extracellular vesicles with continuous community annotation. PLoS Biol 2012; 10(12): e1001450. doi: 10.1371/journal.pbio.1001450 PMID: 23271954Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654-9. doi: 10.1038/ncb1596 PMID: 17486113Record M, Subra C, Silvente-Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol 2011; 81(10): 1171-82. doi: 10.1016/j.bcp.2011.02.011 PMID: 21371441Futter CE, White IJ. Annexins and Endocytosis. Traffic 2007; 8(8): 951-8. doi: 10.1111/j.1600-0854.2007.00590.x PMID: 17547702Gastpar R, Gehrmann M, Bausero MA, et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 2005; 65(12): 5238-47. doi: 10.1158/0008-5472.CAN-04-3804 PMID: 15958569Nguyen DG, Booth A, Gould SJ, Hildreth JEK. Evidence that HIV budding in primary macrophages occurs through the exosome release pathway. J Biol Chem 2003; 278(52): 52347-54. doi: 10.1074/jbc.M309009200 PMID: 14561735Mears R, Craven RA, Hanrahan S, et al. Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics 2004; 4(12): 4019-31. doi: 10.1002/pmic.200400876 PMID: 15478216Hegmans JPJJ, Bard MPL, Hemmes A, et al. Proteomic analysis of exosomes secreted by human mesothelioma cells. Am J Pathol 2004; 164(5): 1807-15. doi: 10.1016/S0002-9440(10)63739-X PMID: 15111327de Gassart A, Géminard C, Février B, Raposo G, Vidal M. Lipid raft-associated protein sorting in exosomes. Blood 2003; 102(13): 4336-44. doi: 10.1182/blood-2003-03-0871 PMID: 12881314Antimisiaris S, Mourtas S, Marazioti A. Exosomes and exosomeinspired vesicles for targeted drug delivery. Pharmaceutics 2018; 10(4): 218. doi: 10.3390/pharmaceutics10040218 PMID: 30404188Parolini I, Federici C, Raggi C, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 2009; 284(49): 34211-22. doi: 10.1074/jbc.M109.041152 PMID: 19801663Piccin A, Murphy WG, Smith OP. Circulating microparticles: Pathophysiology and clinical implications. Blood Rev 2007; 21(3): 157-71. doi: 10.1016/j.blre.2006.09.001 PMID: 17118501Subra C, Laulagnier K, Perret B, Record M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007; 89(2): 205-12. doi: 10.1016/j.biochi.2006.10.014Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: applications in regenerative medicine. Cells 2021; 10(8): 1959. doi: 10.3390/cells10081959 PMID: 34440728Blanchard N, Lankar D, Faure F, et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/ζ complex. J Immun 2002; 168(7): 3235-41. doi: 10.4049/jimmunol.168.7.3235Monypenny J, Milewicz H, Flores-Borja F, et al. ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation. Cell Rep 2018; 24(3): 630-41. doi: 10.1016/j.celrep.2018.06.066 PMID: 30021161Roucourt B, Meeussen S, Bao J, Zimmermann P, David G. Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res 2015; 25(4): 412-28. doi: 10.1038/cr.2015.29 PMID: 25732677Liu H, Chen L, Peng Y, et al. Dendritic cells loaded with tumor derived exosomes for cancer immunotherapy. Oncotarget 2018; 9(2): 2887-94. doi: 10.18632/oncotarget.20812 PMID: 29416821Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids.Curr Protoc Cell Biol 2006; 30(1): 3.22.1-3.22.29. doi: 10.1002/0471143030.cb0322s30Livshits MA, Khomyakova E, Evtushenko EG, et al. Isolation of exosomes by differential centrifugation: Theoretical analysis of a commonly used protocol. Sci Rep 2015; 5(1): 17319. doi: 10.1038/srep17319 PMID: 26616523Momen-Heravi F. Isolation of extracellular vesicles by ultracentrifugation, Extracellular Vesicles. Methods Mol Biol 2017; 1660: 25-32. doi: 10.1007/978-1-4939-7253-1_3 PMID: 28828645Kang YT, Kim YJ, Bu J, Cho YH, Han SW, Moon BI. High-purity capture and release of circulating exosomes using an exosomespecific dual-patterned immunofiltration (ExoDIF) device. Nanoscale 2017; 9(36): 13495-505. doi: 10.1039/C7NR04557C PMID: 28862274Liu F, Vermesh O, Mani V, et al. The exosome total isolation chip. ACS nano 2017; 11(11): 10712-23. 7 doi: 10.1021/acsnano.7b04878Wunsch BH, Smith JT, Gifford SM, et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nat Nanotechnol 2016; 11(11): 936-40. doi: 10.1038/nnano.2016.134 PMID: 27479757Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev 2016; 106((Pt A)): 148-56. doi: 10.1016/j.addr.2016.02.006 PMID: 26928656Gu Y, Chen C, Mao Z, et al. Acoustofluidic centrifuge for nanoparticle enrichment and separation. Sci Adv 2021; 7(1): eabc0467. doi: 10.1126/sciadv.abc0467 PMID: 33523836Shi L, Kuhnell D, Borra VJ, Langevin SM, Nakamura T, Esfandiari L. Rapid and label-free isolation of small extracellular vesicles from biofluids utilizing a novel insulator based dielectrophoretic device. Lab Chip 2019; 19(21): 3726-34. doi: 10.1039/C9LC00902G PMID: 31588942Hassanpour Tamrin S, Sanati Nezhad A, Sen A. Label-free isolation of exosomes using microfluidic technologies. ACS Nano 2021; 15(11): 17047-79. doi: 10.1021/acsnano.1c03469 PMID: 34723478Zhang M, Jin K, Gao L, et al. Methods and technologies for exosome isolation and characterization. Small Methods 2018; 2(9): 1800021. doi: 10.1002/smtd.201800021Yang XX, Sun C, Wang L, Guo XL. New insight into isolation, identification techniques and medical applications of exosomes. J Control Release 2019; 308: 119-29. doi: 10.1016/j.jconrel.2019.07.021 PMID: 31325471Böing AN, van der Pol E, Grootemaat AE, Coumans FAW, Sturk A, Nieuwland R. Single-step isolation of extracellular vesicles by size-exclusion chromatography. J Extracell Vesicles 2014; 3(1): 23430.Cvjetkovic A, Lötvall J, Lässer C. The influence of rotor type and centrifugation time on the yield and purity of extracellular vesicles. J Extracell Vesicles 2014; 3(1): 23111. doi: 10.3402/jev.v3.23111 PMID: 24678386Tauro BJ, Greening DW, Mathias RA, et al. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods 2012; 56(2): 293-304. doi: 10.1016/j.ymeth.2012.01.002 PMID: 22285593Xu X, Liu Y, Li Y, et al. Selective exosome exclusion of miR-375 by glioma cells promotes glioma progression by activating the CTGF-EGFR pathway. J Exp Clin Cancer Res 2021; 40(1): 16. doi: 10.1186/s13046-020-01810-9 PMID: 33407703Doldán. Fagúndez, Cayota A, Laíz J, Tosar JP. Electrochemical sandwich immunosensor for determination of exosomes based on surface markermediated signal amplification. Anal Chem 2016; 88: 10466-73. doi: 10.1021/acs.analchem.6b02421 PMID: 27734678Cheruvanky A, Zhou H, Pisitkun T, et al. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am J Physiol Renal Physiol 2007; 292(5): F1657-61. doi: 10.1152/ajprenal.00434.2006 PMID: 17229675Takov K, Yellon DM, Davidson SM. Comparison of small extracellular vesicles isolated from plasma by ultracentrifugation or size-exclusion chromatography: Yield, purity and functional potential. J Extracell Vesicles 2019; 8(1): 1560809. doi: 10.1080/20013078.2018.1560809 PMID: 30651940Bohmer N, Demarmels N, Tsolaki E, et al. Removal of cells from body fluids by magnetic separation in batch and continuous mode: Influence of bead size, concentration, and contact time. ACS Appl Mater Interfaces 2017; 9(35): 29571-9. doi: 10.1021/acsami.7b10140 PMID: 28805365Lee S, Tae S, Jee N, Shin S. LDA-based model for measuring impact of change orders in apartment projects and its application for prerisk assessment and postevaluation. J Constr Eng Manage 2015; 141(7): 04015011. doi: 10.1061/(ASCE)CO.1943-7862.0000971Aghilinejad A, Aghaamoo M, Chen X, Xu J. Effects of electrothermal vortices on insulator-based dielectrophoresis for circulating tumor cell separation. Electrophoresis 2018; 39(5-6): 869-77. doi: 10.1002/elps.201700264 PMID: 28975645Ibsen SD, Wright J, Lewis JM, et al. Rapid isolation and detection of exosomes and associated biomarkers from plasma. ACS Nano 2017; 11(7): 6641-51. doi: 10.1021/acsnano.7b00549 PMID: 28671449Zeming KK, Thakor NV, Zhang Y, Chen CH. Real-time modulated nanoparticle separation with an ultra-large dynamic range. Lab Chip 2016; 16(1): 75-85. doi: 10.1039/C5LC01051A PMID: 26575003Wunsch BH, Smith JT, Gifford SM, et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nat Nanotechnol 2016; 11(11): 936-40. doi: 10.1038/nnano.2016.134 PMID: 27479757Malhotra H, Sheokand N, Kumar S, et al. Exosomes: Tunable nano vehicles for macromolecular delivery of transferrin and lactoferrin to specific intracellular compartment. JBN 2016; 12(5): 1101-14. doi: 10.1166/jbn.2016.2229Rupert DLM, Claudio V, Lässer C, Bally M. Methods for the physical characterization and quantification of extracellular vesicles in biological samples. Biochim Biophys Acta, Gen Subj 2017; 1861(1): 3164-79. doi: 10.1016/j.bbagen.2016.07.028 PMID: 27495390Zhang M, Zang X, Wang M, et al. Exosome-based nanocarriers as bio-inspired and versatile vehicles for drug delivery: Recent advances and challenges. J Mater Chem B Mater Biol Med 2019; 7(15): 2421-33. doi: 10.1039/C9TB00170K PMID: 32255119Peng H, Ji W, Zhao R, et al. Exosome: A significant nano-scale drug delivery carrier. J Mater Chem B Mater Biol Med 2020; 8(34): 7591-608. doi: 10.1039/D0TB01499K PMID: 32697267Ludwig N, Whiteside TL, Reichert TE. Challenges in exosome isolation and analysis in health and disease. Int J Mol Sci 2019; 20(19): 4684. doi: 10.3390/ijms20194684 PMID: 31546622Lee M, Ban JJ, Im W, Kim M. Influence of storage condition on exosome recovery. Biotechnol Bioprocess Eng; BBE 2016; 21(2): 299-304. doi: 10.1007/s12257-015-0781-xCharoenviriyakul C, Takahashi Y, Nishikawa M, Takakura Y. Preservation of exosomes at room temperature using lyophilization. Int J Pharm 2018; 553(1-2): 1-7. doi: 10.1016/j.ijpharm.2018.10.032 PMID: 30316791Shin K-O, Ha DH, Kim JO, et al. Exosomes from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by inducing de novo synthesis of ceramides in atopic dermatitis. Cells 2020; 9(3): 680.Sophie N. Dermatitis atópica: Epidemiología global y factores de riesgo. Ann Nutr Metab 2015; 66(S1): 8-16.Leung DYM. Atopic dermatitis: New insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 2000; 105(5): 860-76. doi: 10.1067/mai.2000.106484 PMID: 10808164Leung DYM. New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int 2013; 62(2): 151-61. doi: 10.2332/allergolint.13-RAI-0564 PMID: 23712284Sullivan M, Silverberg NB. Current and emerging concepts in atopic dermatitis pathogenesis. Clin Dermatol 2017; 35(4): 349-53. doi: 10.1016/j.clindermatol.2017.03.006 PMID: 28709564Irvine AD, Irwin McLean WH. Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis. J Invest Dermatol 2006; 126(6): 1200-2. doi: 10.1038/sj.jid.5700365 PMID: 16702964Mendt M, Kamerkar S, Sugimoto H, et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 2018; 3(8): e99263. doi: 10.1172/jci.insight.99263 PMID: 29669940Cho BS, Kim JO, Ha DH, Yi YW. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cell Res Ther 2018; 9(1): 187. doi: 10.1186/s13287-018-0939-5 PMID: 29996938Snast I, Reiter O, Hodak E, Friedland R, Mimouni D, Leshem YA. Are biologics efficacious in atopic dermatitis? A systematic review and meta-analysis. Am J Clin Dermatol 2018; 19(2): 145-65. doi: 10.1007/s40257-017-0324-7 PMID: 29098604Prussin C, Metcalfe DD. 4. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2003; 111(2): S486-94. doi: 10.1067/mai.2003.120Liu FT, Goodarzi H, Chen HY. IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol 2011; 41(3): 298-310. doi: 10.1007/s12016-011-8252-4 PMID: 21249468Wollenberg A, Oppel T, Schottdorf E-M, Günther S, Moderer M, Mommaas M. Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases. J Invest Dermatol 2002; 118(2): 327-34. doi: 10.1046/j.0022-202x.2001.01665.x PMID: 11841552Schuller E, Teichmann B, Haberstok J, Moderer M, Bieber T, Wollenberg A. In situ expression of the costimulatory molecules CD80 and CD86 on Langerhans cells and inflammatory dendritic epidermal cells (IDEC) in atopic dermatitis. Arch Dermatol Res 2001; 293(9): 448-54. doi: 10.1007/s004030100263 PMID: 11758787Proksch E, Brandner JM, Jensen JM. The skin: An indispensable barrier. Exp Dermatol 2008; 17(12): 1063-72. doi: 10.1111/j.1600-0625.2008.00786.x PMID: 19043850Wang M, Zhao Y, Zhang Q. Human mesenchymal stem cellderived exosomes accelerate wound healing of mice eczema. J Dermatolog Treat 2020; 1-5. doi: 10.1080/09546634.2020.1820935 PMID: 32893705Verhagen J, Akdis M, Traidlhoffmann C, et al. Absence of Tregulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol 2006; 117(1): 176-83. doi: 10.1016/j.jaci.2005.10.040 PMID: 16387603Mohr A, Atif M, Balderas R, Gorochov G, Miyara M. The role of FOXP3+ regulatory T cells in human autoimmune and inflammatory diseases. Clin Exp Immunol 2019; 197(1): 24-35. doi: 10.1111/cei.13288Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005; 366(9498): 1736-43. doi: 10.1016/S0140-6736(05)67700-8 PMID: 16291068Park KY, Han HS, Park JW, Kwon HH, Park GH, Seo SJ. Exosomes derived from human adipose tissue derived mesenchymal stem cells for the treatment of dupilumab‐related facial redness in patients with atopic dermatitis: a report of two cases. J Cosmet Dermatol 2022; 21(2): 844-9. doi: 10.1111/jocd.14153Mallipeddi R. Epidermolysis bullosa and cancer. Clin Exp Dermatol 2002; 27(8): 616-23. doi: 10.1046/j.1365-2230.2002.01130.x PMID: 12472531Pitt JM, André F, Amigorena S, et al. Dendritic cell–derived exosomes for cancer therapy. JCI 2016 Apr 1; 126(4): 1224-32.Lolli F, Pallotti F, Rossi A, et al. Androgenetic alopecia: A review. Endocrine 2017; 57(1): 9-17. doi: 10.1007/s12020-017-1280-y PMID: 28349362Slominski A, Paus R, Plonka P, et al. Melanogenesis during the anagen-catagen-telogen transformation of the murine hair cycle. J Invest Dermatol 1994; 102(6): 862-9. doi: 10.1111/1523-1747.ep12382606 PMID: 8006449Cash TF. The psychosocial consequences of androgenetic alopecia: A review of the research literature. Br J Dermatol 1999; 141(3): 398-405. doi: 10.1046/j.1365-2133.1999.03030.x PMID: 10583042Mohammadi P, Youssef KK, Abbasalizadeh S, Baharvand H, Aghdami N. Human hair reconstruction: Close, but yet so far. Stem Cells Dev 2016; 25(23): 1767-79. doi: 10.1089/scd.2016.0137 PMID: 27649771Owczarczyk-Saczonek A, Krajewska-Włodarczyk M, Kruszewska A, et al. Therapeutic potential of stem cells in follicle regeneration. Stem Cells Int 2018; 2018: 1-16. doi: 10.1155/2018/1049641 PMID: 30154860Kanti V, Messenger A, Dobos G, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men - short version. J Eur Acad Dermatol Venereol 2018; 32(1): 11-22. doi: 10.1111/jdv.14624 PMID: 29178529Ajit A, Nair MD, Venugopal B. Exploring the Potential of Mesenchymal Stem Cell–Derived Exosomes for the Treatment of Alopecia. Regen Eng Transl Med 2021; 7(2): 119-28. doi: 10.1007/s40883-021-00204-3Rajendran RL, Gangadaran P, Bak SS, et al. Extracellular vesicles derived from MSCs activates dermal papilla cell in vitro and promotes hair follicle conversion from telogen to anagen in mice. Sci Rep 2017; 7(1): 15560. doi: 10.1038/s41598-017-15505-3 PMID: 29138430Zhou L, Wang H, Jing J, Yu L, Wu X, Lu Z. Regulation of hair follicle development by exosomes derived from dermal papilla cells. Biochem Biophys Res Commun 2018; 500(2): 325-32. doi: 10.1016/j.bbrc.2018.04.067 PMID: 29654758Limat A, Breitkreutz D, Stark HJ, et al. Experimental modulation of the differentiated phenotype of keratinocytes from epidermis andhair follicle outer root sheath and matrix cells. Ann N Y Acad Sci 1991; 642(1): 125-46. doi: 10.1111/j.1749-6632.1991.tb24385.x PMID: 1725578Taylor M, Ashcroft ATT, Westgate GE, Gibson WT, Messenger AG. Glycosaminoglycan synthesis by cultured human hair follicle dermal papilla cells: Comparison with non-follicular dermal fibroblasts. Br J Dermatol 1992; 126(5): 479-84. doi: 10.1111/j.1365-2133.1992.tb15120.x PMID: 1610689Limat A, Hunziker T, Waelti ER, Inaebnit SP, Wiesmann U, Braathen LR. Soluble factors from human hair papilla cells and dermal fibroblasts dramatically increase the clonal growth of outer root sheath cells. Arch Dermatol Res 1993; 285(4): 205-10. doi: 10.1007/BF00372010 PMID: 8342964Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol 2002; 118(2): 216-25. doi: 10.1046/j.0022-202x.2001.01670.x PMID: 11841536Burke J, Kolhe R, Hunter M, Isales C, Hamrick M, Fulzele S. Stem cell-derived exosomes: A potential alternative therapeutic agent in orthopaedics. Stem Cells Int 2016; 2016: 1-6. doi: 10.1155/2016/5802529 PMID: 26904130Wong T, Gammon L, Liu L, et al. Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol 2008; 128(9): 2179-89. doi: 10.1038/jid.2008.78 PMID: 18385758Rashidghamat E, McGrath JA. Novel and emerging therapies in the treatment of recessive dystrophic epidermolysis bullosa. Intractable Rare Dis Res 2017; 6(1): 6-20. doi: 10.5582/irdr.2017.01005 PMID: 28357176Mallipeddi R. Epidermolysis bullosa and cancer. Clin Exp Dermatol 2002; 27(8): 616-23. doi: 10.1046/j.1365-2230.2002.01130.x PMID: 12472531McBride JD, Rodriguez-Menocal L, Candanedo A, Guzman W, Garcia-Contreras M, Badiavas EV. Dual mechanism of type VII collagen transfer by bone marrow mesenchymal stem cell extracellular vesicles to recessive dystrophic epidermolysis bullosa fibroblasts. Biochimie 2018; 155: 50-8. doi: 10.1016/j.biochi.2018.04.007 PMID: 29653141Tanabe T, Maeda M, Saito K, Katada T. Dual function of cTAGE5 in collagen export from the endoplasmic reticulum. Mol Biol Cell 2016; 27(13): 2008-13. doi: 10.1091/mbc.E16-03-0180 PMID: 27170179Malhotra V, Erlmann P. The pathway of collagen secretion. Annu Rev Cell Dev Biol 2015; 31(1): 109-24. doi: 10.1146/annurev-cellbio-100913-013002 PMID: 26422332Christiano AM, Amano S, Eichenfield LF, Burgeson RE, Uitto J. Premature termination codon mutations in the type VII collagen gene in recessive dystrophic epidermolysis bullosa result in nonsense-mediated mRNA decay and absence of functional protein. J Invest Dermatol 1997; 109(3): 390-4. doi: 10.1111/1523-1747.ep12336276 PMID: 9284110Moon JH, Kwak SS, Park G, et al. Isolation and characterization of multipotent human keloid-derived mesenchymal-like stem cells. Stem Cells Dev 2008; 17(4): 713-24. doi: 10.1089/scd.2007.0210 PMID: 18710345Jannati P, Aref S, Jannati AA, Jannati F, Moravvej H. Comparison of therapeutic response of keloids to cryotherapy plus intralesional triamcinolone acetonide or verapamil hydrochloride. J Skin Stem Cell 2015; 2(1): jssc2928. doi: 10.17795/jssc2928Bayat A, Arscott G, Ollier WER, Mc Grouther DA, Ferguson MWJ. Keloid disease: Clinical relevance of single versus multiple site scars. Br J Plast Surg 2005; 58(1): 28-37. doi: 10.1016/j.bjps.2004.04.024 PMID: 15629164Lee G, Hunter-Smith DJ, Rozen WM. Autologous fat grafting in keloids and hypertrophic scars: A review. Scars Burn Heal 2017; 3. doi: 10.1177/2059513117700157 PMID: 29799555Shih B, Garside E, McGrouther DA, Bayat A. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen 2010; 18(2): 139-53. doi: 10.1111/j.1524-475X.2009.00553.x PMID: 20002895Michael O. The search for the genetic basis of african keloids. Ann Ib Postgrad Med 2012; 10(2): 53-5.Naylor M, Brissett A. Current concepts in the etiology and treatment of keloids. Facial Plast Surg 2012; 28(5): 504-12. doi: 10.1055/s-0032-1325644 PMID: 23027217Clark JA, Turner ML, Howard L, Stanescu H, Kleta R, Kopp JB. Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity. BMC Dermatol 2009; 9(1): 8. doi: 10.1186/1471-5945-9-8 PMID: 19638218Rabello FB, Souza CD, Júnior JAF. Update on hypertrophic scar treatment. Clinics 2014; 69(8): 565-73. doi: 10.6061/clinics/2014(08)11 PMID: 25141117Olaitan P, Olabanji J, Oladele A, Oseni G. Symptomatology of keloids in Africans. J Biomed Res 2013; 5(1): 29-33. PMID: 23554791Gauglitz G, Ngwane S. Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol 2013; 6(2): 103. doi: 10.2147/CCID.S35252Goyal S, Saini I, Goyal S. Familial keloid in Indian Scenario: Case report and review of literature. OAlib 2015; 2(7): 1-4. doi: 10.4236/oalib.1101578Berman B, Elston D. Keloid and Hypertrophic Scar Clinical Presentation Med 2016.Shaheen A, Khaddam J, Kesh F. Risk factors of keloids in Syrians. BMC Dermatol 2016; 16(1): 13. doi: 10.1186/s12895-016-0050-5 PMID: 27646558Marneros AG, Norris JEC, Watanabe S, Reichenberger E, Olsen BR. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol 2004; 122(5): 1126-32. doi: 10.1111/j.0022-202X.2004.22327.x PMID: 15140214Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Mol Med 2011; 17(1-2): 113-25. doi: 10.2119/molmed.2009.00153 PMID: 20927486Mandal A, Imran D, Rao GS. Spontaneous keloids in siblings. Ir Med J 2004; 97(8): 250-1. PMID: 15532974Cheraghi N, Cognetta A Jr, Goldberg D. Radiation therapy for the adjunctive treatment of surgically excised keloids: a review. J Clin Aesthet Dermatol 2017; 10(8): 12-5. PMID: 28979658Wu ZY, Zhang HJ, Zhou ZH, et al. The effect of inhibiting exosomes derived from adipose-derived stem cells via the TGFβ1/Smad pathway on the fibrosis of keloid fibroblasts. Gland Surg 2021; 10(3): 1046-56. doi: 10.21037/gs-21-4 PMID: 33842249Hata A, Chen YG. TGF-β signaling from receptors to Smads. Cold Spring Harb Perspect Biol 2016; 8(9): a022061. doi: 10.1101/cshperspect.a022061 PMID: 27449815Meng XM, Tang PMK, Li J, Lan HY. TGF-Î2/Smad signaling in renal fibrosis. Front Physiol 2015; 6: 82. doi: 10.3389/fphys.2015.00082 PMID: 25852569Xu F, Liu C, Zhou D, Zhang L. TGF-β/SMAD pathway and its regulation in hepatic fibrosis. J Histochem Cytochem 2016; 64(3): 157-67. doi: 10.1369/0022155415627681 PMID: 26747705Fang S, Xu C, Zhang YT, et al. Umbilical cord derived mesenchymal stem cell-derived exosomal micrornas suppress myofibroblast differentiation by inhibiting the transforming growth factor-oblasts fibroblast functionnd healing. Stem Cells Transl Med 2016; 5: 1425-39. doi: 10.5966/sctm.2015-0367 PMID: 27388239Litin SC. Mayo Clinic Family Health Book. 5th Edition: Completely Revised and Updated. RochesterMN: Mayo Clinic Press 2018.Berwick M, Erdei E, Hay J. Melanoma epidemiology and public health. Dermatol Clin 2009 Apr 1; 27(2): 205-14.Balch CM, Gershenwald JE, Soong S, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27(36): 6199-206. doi: 10.1200/JCO.2009.23.4799 PMID: 19917835Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: Systematic review and meta-analysis. BMJ 2012; 345(jul24 2): e4757. doi: 10.1136/bmj.e4757 PMID: 22833605Rhodes AR, Weinstock MA, Fitzpatrick TB, Mihm MC Jr, Sober AJ. Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals. JAMA 1987; 258(21): 3146-54. doi: 10.1001/jama.1987.03400210088032 PMID: 3312689Oliveria SA, Saraiya M, Geller AC, Heneghan MK, Jorgensen C. Sun exposure and risk of melanoma. Arch Dis Child 2005; 91(2): 131-8. doi: 10.1136/adc.2005.086918 PMID: 16326797Azoury SC, Lange JR. Epidemiology, risk factors, prevention, and early detection of melanoma. Surg Clin North Am 2014; 94(5): 945-62. vii doi: 10.1016/j.suc.2014.07.013 PMID: 25245960Perkins A, Duffy RL. Atypical moles: Diagnosis and management. AFP 2015; 91(11): 762-7. PMID: 26034853Chin L, Garraway LA, Fisher DE. Malignant melanoma: Genetics and therapeutics in the genomic era. Genes Dev 2006; 20(16): 2149-82. doi: 10.1101/gad.1437206 PMID: 16912270Balsamo M, Pietra G, Vermi W, Moretta L, Mingari MC, Vitale M. Melanoma immunoediting by NK cells. OncoImmunology 2012; 1(9): 1607-9. doi: 10.4161/onci.21456 PMID: 23264909Sconocchia G, Arriga R, Tornillo L, Terracciano L, Ferrone S, Spagnoli GC. Melanoma cells inhibit NK cell functions. Cancer Res 2012; 72(20): 5428-9. doi: 10.1158/0008-5472.CAN-12-1181 PMID: 23047870Kalimuthu S, Gangadaran P, Li XJ, et al. In vivo therapeutic potential of mesenchymal stem cell-derived extracellular vesicles with optical imaging reporter in tumor mice model. Sci Rep 2016; 6(1): 30418. doi: 10.1038/srep30418 PMID: 27452924Escudier B, Dorval T, Chaput N, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derivedexosomes: Results of thefirst phase I clinical trial. J Transl Med 2005; 3(1): 10. doi: 10.1186/1479-5876-3-10 PMID: 15740633Zhu L, Kalimuthu S, Gangadaran P, et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics 2017; 7(10): 2732-45. doi: 10.7150/thno.18752 PMID: 28819459Shimasaki N, Coustan-Smith E, Kamiya T, Campana D. Expanded and armed natural killer cells for cancer treatment. Cytotherapy 2016; 18(11): 1422-34. doi: 10.1016/j.jcyt.2016.06.013 PMID: 27497701Hellström I, Hellström KE. Cytotoxic effect of lymphocytes from pregnant mice on cultivated tumor cells. I. Specificity, nature of effector cells and blocking by serum. Int J Cancer 1975; 15(1): 1-16. doi: 10.1002/ijc.2910150102 PMID: 1168624Fais S. NK cell-released exosomes. OncoImmunology 2013; 2(1): e22337. doi: 10.4161/onci.22337 PMID: 23482694Katakowski M, Buller B, Zheng X, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 2013; 335(1): 201-4. doi: 10.1016/j.canlet.2013.02.019 PMID: 23419525Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295(5562): 2097-100. doi: 10.1126/science.1068440 PMID: 11896281Chen X, Han J, Chu J, et al. A combinational therapy of EGFRCAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 2016; 7(19): 27764-77. doi: 10.18632/oncotarget.8526 PMID: 27050072Augstein P, Heinke P, Schober C, Salzsieder E. Impact of cytokineand FasL-induced apoptosis in the β-cell line NIT-1. Horm Metab Res 2009; 41(3): 207-12. doi: 10.1055/s-0028-1093343 PMID: 18975252Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 2016; 17(9): 1025-36. doi: 10.1038/ni.3518 PMID: 27540992Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2(10): 735-47. doi: 10.1038/nri911 PMID: 12360212Harden JL, Krueger JG, Bowcock AM. The immunogenetics of Psoriasis: A comprehensive review. J Autoimmun 2015; 64: 66-73. doi: 10.1016/j.jaut.2015.07.008 PMID: 26215033Deng Y, Chang C, Lu Q. The inflammatory response in psoriasis: A comprehensive review. Clin Rev Allergy Immunol 2016; 50(3): 377-89. doi: 10.1007/s12016-016-8535-x PMID: 27025861Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: A review. JAMA 2020; 323(19): 1945-60. doi: 10.1001/jama.2020.4006 PMID: 32427307World Health Organization. Global report on psoriasis 2016. Available from http://apps. who. int/iris/handle/10665/204417Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol 2017; 31(2): 205-12. doi: 10.1111/jdv.13854 PMID: 27573025Boehncke WH, Schön MP. Psoriasis. Lancet 2015; 386(9997): 983-94. doi: 10.1016/S0140-6736(14)61909-7 PMID: 26025581Augustin M, Glaeske G, Radtke MA, Christophers E, Reich K, Schäfer I. Epidemiology and comorbidity of psoriasis in children. Br J Dermatol 2010; 162(3): 633-6. doi: 10.1111/j.1365-2133.2009.09593.x PMID: 19922529Huerta C, Rivero E, Rodríguez LAG. Incidence and risk factors for psoriasis in the general population. Arch Dermatol 2007; 143(12): 1559-65. doi: 10.1001/archderm.143.12.1559 PMID: 18087008Brandon A, Mufti A, Gary Sibbald R. Diagnosis and management of cutaneous psoriasis: a review. Adv Skin Wound Care 2019; 32(2): 58-69. doi: 10.1097/01.ASW.0000550592.08674.43 PMID: 30653184Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci 2019; 20(6): 1475. doi: 10.3390/ijms20061475 PMID: 30909615Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician 2017; 63(4): 278-85. PMID: 28404701Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol 1996; 10(6): 369-75. doi: 10.1155/1996/213596 PMID: 9193771Zhang B, Lai RC, Sim WK, Choo ABH, Lane EB, Lim SK. Topical application of mesenchymal stem cell exosomes alleviates the imiquimod induced psoriasis-like inflammation. Int J Mol Sci 2021; 22(2): 720. doi: 10.3390/ijms22020720 PMID: 33450859Dahl MV, Lindroos WE, Nelson RD. Chemokinetic and chemotactic factors in psoriasis scale extracts. J Invest Dermatol 1978; 71(6): 402-6. doi: 10.1111/1523-1747.ep12558281 PMID: 722120Weiss VC, van Den Broek H, Barrett S, West DP. Immunopathology of psoriasis: a comparison with other parakeratotic lesions. J Invest Dermatol 1982; 78(3): 256-60. doi: 10.1111/1523-1747.ep12506623 PMID: 7057057Terui T, Kato T, Tagami H. Stratum corneum activation of complement through the antibody-independent alternative pathway. J Invest Dermatol 1989; 92(4): 593-7. doi: 10.1111/1523-1747.ep12709634 PMID: 2649596Zhang Y, Yan J, Li Z, Zheng J, Sun Q. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate psoriasislike skin inflammation. J Interferon Cytokine Res 2022; 42(1): 8-18. doi: 10.1089/jir.2021.0146 PMID: 35041513Zhu Z, Tang H, Zhu Y, Wang H, Shen Y. Exosomes From ADSCs Attenuate Bleomycin-Induced Skin Fibrosis And Oxidative Stress In Scleroderma via Circ-Zfyve9 Delivery 2021. Available from https://www.researchsquare.com/article/rs-551751/v1 doi: 10.21203/rs.3.rs-551751/v1Yamamoto T, Takagawa S, Katayama I, et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 1999; 112(4): 456-62. doi: 10.1046/j.1523-1747.1999.00528.x PMID: 10201529Allanore Y, Distler O. Advances in cohort enrichment shape future of trial design. Nat Rev Rheumatol 2015; 11(2): 72-4. doi: 10.1038/nrrheum.2014.222 PMID: 25561368Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69(10): 1809-15. doi: 10.1136/ard.2009.114264 PMID: 20551155Shah AA, Wigley FM. My approach to the treatment of scleroderma. Mayo Clin Proc 2013; 88(4): 377-93. doi: 10.1016/j.mayocp.2013.01.018Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev 2010; 9(5): A311-8. doi: 10.1016/j.autrev.2009.11.003 PMID: 19906362Hussein M, Hassan H, Hofny E, et al. Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1β, and tumour necrosis factor α in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol 2005; 58(2): 178-84. doi: 10.1136/jcp.2004.019224Gustafsson R, Tötterman TH, Klareskog L, Hällgren R. Increase in activated T cells and reduction in suppressor inducer T cells in systemic sclerosis. Ann Rheum Dis 1990; 49(1): 40-5. doi: 10.1136/ard.49.1.40 PMID: 2138008Riccieri V, Parisi G, Spadaro A, et al. Reduced circulating natural killer T cells and gamma/delta T cells in patients with systemic sclerosis. J Rheumatol 2005; 32(2): 283-6. PMID: 15693088Masi AT. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23(5): 581-90. doi: 10.1002/art.1780230510 PMID: 7378088Zuber JP, Spertini F. Immunological basis of systemic sclerosis. Rheumatology 2006; 45 (Suppl. 3): 23-5. doi: 10.1093/rheumatology/kel285 PMID: 16987826Artlett CM. Immunology of systemic sclerosis. Front Biosci 2005; 10(1-3): 1707-19. doi: 10.2741/1654 PMID: 15769660Wei J, Bhattacharyya S, Tourtellotte WG, Varga J. Fibrosis in systemic sclerosis: Emerging concepts and implications for targeted therapy. Autoimmun Rev 2011; 10(5): 267-75. doi: 10.1016/j.autrev.2010.09.015 PMID: 20863909Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 2007; 117(3): 557-67. doi: 10.1172/JCI31139 PMID: 17332883Higashi-Kuwata N, Jinnin M, Makino T, et al. Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther 2010; 12(4): R128. doi: 10.1186/ar3066 PMID: 20602758Huang J, Maier C, Zhang Y, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis 2017; 76(11): 1941-8. doi: 10.1136/annrheumdis-2016-210823 PMID: 28814429Colletti M, Galardi A. Santis Exosomes in systemic sclerosis: messengers between immune, vascular and fibrotic components? Int J Mol Sci 2019; 20(18): 4337. doi: 10.3390/ijms20184337 PMID: 31487964Jin J, Qingjian O, Wang Z, et al. BMSC-Derived exosomes intervened the pathogenic changes of scleroderma in mouse through its microRNAs 2021. Available from https://www.researchsquare. com/article/rs-222441/v1 doi: 10.21203/rs.3.rs-222441/v1Lee H, Han S, Kwon CS, Lee D. Biogenesis and regulation of the let-7 miRNAs and their functional implications. Protein Cell 2016; 7(2): 100-13. doi: 10.1007/s13238-015-0212-y PMID: 26399619