Wound Healing Properties of Exosomes — A Review and Modelling
of Combinatorial Analysis Strategies

Fong    Fong    Liew; Boon    Cheng    Chew; Der    Jiun    Ooi
Abstract

Wound healing is an elaborated process, well-regulated via cell migration and proliferation. Although the physiological basics of wound healing have been thoroughly investigated and reported, much remains to be studied. Particularly, various studies have demonstrated the immunomodulatory roles of exosomes derived from plant cells, mammalian cells, and mesenchymal stem cells (MSCs) in the healing and repairing system. The paracrine and therapeutic effects of exosomes are mainly associated with the broad exosomal cargo content comprising growth factors, cytokines, enzymes, nucleic acids, proteins, and lipid signaling molecules. Nevertheless, the functional or mechanism pathway of exosomes with reference to overall exosomal cargo remains undetermined. To date, combinatorial analysis strategies employing Database for Annotation, Visualization, and Integrated Discovery (DAVID), STRING tools, Gene Ontology (GO), Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway enrichment analysis, as well as Ingenuity Pathway Analysis (IPA) have been applied in elucidating network interaction and functional pathway of exosomes. In this review paper, the application of combinatorial analysis strategies is demonstrated to better understand the therapeutic potentials of exosomes in the wound healing process. In conclusion, functional modulation of exosomal cargo for specific biological treatment is achievable, and modelling of combinatorial analysis strategies will hopefully bridge the research gap and provide a paradigm shift to regenerative processes.
Keywords: Exosome, healing, combinatorial analysis, STRING tools, gene ontologY, KEGG pathway, DAVID and ingenuity pathway analysis
[1] 
Harding 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.
[http://dx.doi.org/10.1083/jcb.97.2.329] [PMID:  6309857] 
[2] 
Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. N Engl J Med  2018; 379(10): 958-66.
[http://dx.doi.org/10.1056/NEJMra1704286] [PMID:  30184457] 
[3] 
Kalluri R. The biology and function of exosomes in cancer. J Clin Invest  2016; 126(4): 1208-15.
[http://dx.doi.org/10.1172/JCI81135] [PMID:  27035812] 
[4] 
Maacha S, Bhat AA, Jimenez L, et al. Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance. Mol Cancer  2019; 18(1): 55.
[http://dx.doi.org/10.1186/s12943-019-0965-7] [PMID:  30925923] 
[5] 
Joo HS, Suh JH, Lee HJ, Bang ES, Lee JM. Current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent. Int J Mol Sci  2020; 21(3): 727.
[http://dx.doi.org/10.3390/ijms21030727] [PMID:  31979113] 
[6] 
Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics  2015; 13(1): 17-24.
[http://dx.doi.org/10.1016/j.gpb.2015.02.001] [PMID:  25724326] 
[7] 
Sager R, Palade GE. Structure and development of the chloroplast in Chlamydomonas. I. The normal green cell. J Biophys Biochem Cytol  1957; 3(3): 463-88.
[http://dx.doi.org/10.1083/jcb.3.3.463] [PMID:  13438931] 
[8] 
Girbardt M. About the substructure of Polystictus versicolor L. Arch Mikrobiol  1958; 28(3): 255-69.
[http://dx.doi.org/10.1007/BF00411497] [PMID:  13534407] 
[9] 
Chatterjee KR, Das Gupta NN, De ML. Electron microscopic observations on the morphology of Mycobacterium leprae. Exp Cell Res  1959; 18(3): 521-7.
[http://dx.doi.org/10.1016/0014-4827(59)90317-9] [PMID:  13809448] 
[10] 
Straus W. Occurrence of phagosomes and phago-lysosomes in different segments of the nephron in relation to the reabsorption, transport, digestion, and extrusion of intravenously injected horseradish peroxidase. J Cell Biol  1964; 21(3): 295-308.
[http://dx.doi.org/10.1083/jcb.21.3.295] [PMID:  14189907] 
[11] 
Jensen WA. The composition and ultrastructure of the nucellus in cotton. J Ultrastruct Res  1965; 13(1-2): 112-28.
[http://dx.doi.org/10.1016/S0022-5320(65)80092-2] 
[12] 
Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol  1967; 13(3): 269-88.
[http://dx.doi.org/10.1111/j.1365-2141.1967.tb08741.x] [PMID:  6025241] 
[13] 
Gibson RK, Peberdy JF. Fine structure of protoplasts of Aspergillus nidulans. J Gen Microbiol  1972; 72(3): 529-38.
[http://dx.doi.org/10.1099/00221287-72-3-529] [PMID:  4564688] 
[14] 
Takeo K, Uesaka I, Uehira K, Nishiura M. Fine structure of Cryptococcus neoformans grown in vivo as observed by freeze-etching. J Bacteriol  1973; 113(3): 1449-54.
[http://dx.doi.org/10.1128/JB.113.3.1449-1454.1973] [PMID:  4570787] 
[15] 
Chigaleĭchik AG, Belova LA, Grishchenko VM, Rylkin SS. Several properties of the extracellular vesicles of Candida tropicalis yeasts grown on n-alkanes. Mikrobiologiia  1977; 46(3): 467-71.
[PMID: 895555] 
[16] 
Pan BT, Teng K, Wu C, Adam M, Johnstone RM. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol  1985; 101(3): 942-8.
[http://dx.doi.org/10.1083/jcb.101.3.942] [PMID:  2993317] 
[17] 
Johnstone 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.
[http://dx.doi.org/10.1016/S0021-9258(18)48095-7] [PMID:  3597417] 
[18] 
Zitvogel L, Regnault A, Lozier A, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med  1998; 4(5): 594-600.
[http://dx.doi.org/10.1038/nm0598-594] [PMID:  9585234] 
[19] 
Wolfers J, Lozier A, Raposo G, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med  2001; 7(3): 297-303.
[http://dx.doi.org/10.1038/85438] [PMID:  11231627] 
[20] 
Valadi 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.
[http://dx.doi.org/10.1038/ncb1596] [PMID:  17486113] 
[21] 
Skog J, Würdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol  2008; 10(12): 1470-6.
[http://dx.doi.org/10.1038/ncb1800] [PMID:  19011622] 
[22] 
Henne WM, Stenmark H, Emr SD. Molecular mechanisms of the membrane sculpting ESCRT pathway. Cold Spring Harb Perspect Biol  2013; 5(9)a016766
[http://dx.doi.org/10.1101/cshperspect.a016766] [PMID:  24003212] 
[23] 
Colombo M, Moita C, van Niel G, et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci  2013; 126(Pt 24): 5553-65.
[http://dx.doi.org/10.1242/jcs.128868] [PMID:  24105262] 
[24] 
Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell  2016; 30(6): 836-48.
[http://dx.doi.org/10.1016/j.ccell.2016.10.009] [PMID:  27960084] 
[25] 
Li C, Hou X, Zhang P, et al. Exosome-based tumor therapy: opportunities and challenges. Curr Drug Metab  2020; 21(5): 339-51.
[http://dx.doi.org/10.2174/1389200221666200515103354] [PMID:  32410558] 
[26] 
Kim YK, Choi Y, Nam GH, Kim IS. Functionalized exosome harboring bioactive molecules for cancer therapy. Cancer Lett  2020; 489: 155-62.
[http://dx.doi.org/10.1016/j.canlet.2020.05.036] [PMID:  32623071] 
[27] 
Hansen LL, Nielsen ME. Plant exosomes: using an unconventional exit to prevent pathogen entry? J Exp Bot  2017; 69(1): 59-68.
[http://dx.doi.org/10.1093/jxb/erx319] [PMID:  29036447] 
[28] 
Yang T, Martin P, Fogarty B, et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res  2015; 32(6): 2003-14.
[http://dx.doi.org/10.1007/s11095-014-1593-y] [PMID:  25609010] 
[29] 
Samuelson I, Vidal-Puig AJ. Fed-EXosome: extracellular vesicles and cell-cell communication in metabolic regulation. Essays Biochem  2018; 62(2): 165-75.
[http://dx.doi.org/10.1042/EBC20170087] [PMID:  29717059] 
[30] 
Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol  2018; 6: 18.
[http://dx.doi.org/10.3389/fcell.2018.00018] [PMID:  29515996] 
[31] 
Hosseini M, Roshangar L, Raeisi S, et al. The therapeutic applications of exosomes in different types of diseases: a review. Curr Mol Med 2020.
[http://dx.doi.org/10.2174/1566524020666200610164743] [PMID:  32520687] 
[32] 
De Toro J, Herschlik L, Waldner C, Mongini C. Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol  2015; 6: 203.
[http://dx.doi.org/10.3389/fimmu.2015.00203] [PMID:  25999947] 
[33] 
Osaki M, Okada F. Exosomes and their role in cancer progression. Yonago Acta Med  2019; 62(2): 182-90.
[http://dx.doi.org/10.33160/yam.2019.06.002] [PMID:  31320822] 
[34] 
Liu W, Bai X, Zhang A, Huang J, Xu S, Zhang J. Role of exosomes in central nervous system diseases. Front Mol Neurosci  2019; 12: 240.
[http://dx.doi.org/10.3389/fnmol.2019.00240] [PMID:  31636538] 
[35] 
Urbanelli L, Buratta S, Tancini B, et al. The role of extracellular vesicles in viral infection and transmission. Vaccines (Basel)  2019; 7(3): 102.
[http://dx.doi.org/10.3390/vaccines7030102] [PMID:  31466253] 
[36] 
Der JE, Dixon WT, Jimbow K, Horikoshi T. A murine monoclonal antibody, MoAb HMSA-5, against a melanosomal component highly expressed in early stages, and common to normal and neoplastic melanocytes. Br J Cancer  1993; 67(1): 47-57.
[http://dx.doi.org/10.1038/bjc.1993.8] [PMID:  7678981] 
[37] 
Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood  1999; 94(11): 3791-9.
[http://dx.doi.org/10.1182/blood.V94.11.3791] [PMID:  10572093] 
[38] 
Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G. First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod  2004; 10(1): 55-63.
[http://dx.doi.org/10.1093/molehr/gah006] [PMID:  14665707] 
[39] 
van Niel G, Raposo G, Candalh C, et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology  2001; 121(2): 337-49.
[http://dx.doi.org/10.1053/gast.2001.26263] [PMID:  11487543] 
[40] 
McKechnie NM, King BC, Fletcher E, Braun G. Fas-ligand is stored in secretory lysosomes of ocular barrier epithelia and released with microvesicles. Exp Eye Res  2006; 83(2): 304-14.
[http://dx.doi.org/10.1016/j.exer.2005.11.028] [PMID:  16563377] 
[41] 
Kuo WP, Tigges JC, Toxavidis V, et al. Red blood cells: a source of extracellular vesicles. Extracellular Vesicles: Methods Mol Biol  2017; 1660: 15-22.
[http://dx.doi.org/10.1007/978-1-4939-7253-1_2] 
[42] 
Wu R, Gao W, Yao K, Ge J. Roles of exosomes derived from immune cells in cardiovascular diseases. Front Immunol  2019; 10: 648.
[http://dx.doi.org/10.3389/fimmu.2019.00648] [PMID:  30984201] 
[43] 
Wei G, Jie Y, Haibo L, et al. Dendritic cells derived exosomes migration to spleen and induction of inflammation are regulated by CCR7. Sci Rep  2017; 7: 42996.
[http://dx.doi.org/10.1038/srep42996] [PMID:  28223684] 
[44] 
Raposo G, Nijman HW, Stoorvogel W, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med  1996; 183(3): 1161-72.
[http://dx.doi.org/10.1084/jem.183.3.1161] [PMID:  8642258] 
[45] 
Lundy SK, Klinker MW, Fox DA. Killer B lymphocytes and their fas ligand positive exosomes as inducers of immune tolerance. Front Immunol  2015; 6: 122.
[http://dx.doi.org/10.3389/fimmu.2015.00122] [PMID:  25852690] 
[46] 
Blanchard 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 Immunol  2002; 168(7): 3235-41.
[http://dx.doi.org/10.4049/jimmunol.168.7.3235] [PMID:  11907077] 
[47] 
Peters PJ, Borst J, Oorschot V, et al. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med  1991; 173(5): 1099-109.
[http://dx.doi.org/10.1084/jem.173.5.1099] [PMID:  2022921] 
[48] 
Majumdar R, Tavakoli Tameh A, Parent CA. Exosomes mediate LTB4 release during neutrophil chemotaxis. PLoS Biol  2016; 14(1)e1002336
[http://dx.doi.org/10.1371/journal.pbio.1002336] [PMID:  26741884] 
[49] 
Skokos D, Le Panse S, Villa I, et al. Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J Immunol  2001; 166(2): 868-76.
[http://dx.doi.org/10.4049/jimmunol.166.2.868] [PMID:  11145662] 
[50] 
Flaumenhaft R, Mairuhu AT, Italiano JE. Platelet- and megakaryocyte-derived microparticles. Semin Thromb Hemost  2010; 36(8): 881-7.
[http://dx.doi.org/10.1055/s-0030-1267042] [PMID:  21049389] 
[51] 
Michael A, Bajracharya SD, Yuen PS, et al. Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis  2010; 16(1): 34-8.
[http://dx.doi.org/10.1111/j.1601-0825.2009.01604.x] [PMID:  19627513] 
[52] 
Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci USA  2004; 101(36): 13368-73.
[http://dx.doi.org/10.1073/pnas.0403453101] [PMID:  15326289] 
[53] 
Srinivasan S, Vannberg FO, Dixon JB. Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node. Sci Rep  2016; 6: 24436.
[http://dx.doi.org/10.1038/srep24436] [PMID:  27087234] 
[54] 
Admyre C, Johansson SM, Qazi KR, et al. Exosomes with immune modulatory features are present in human breast milk. J Immunol  2007; 179(3): 1969-78.
[http://dx.doi.org/10.4049/jimmunol.179.3.1969] [PMID:  17641064] 
[55] 
Vojtech L, Woo S, Hughes S, et al. Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Res  2014; 42(11): 7290-304.
[http://dx.doi.org/10.1093/nar/gku347] [PMID:  24838567] 
[56] 
Asea A, Jean-Pierre C, Kaur P, et al. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol  2008; 79(1): 12-7.
[http://dx.doi.org/10.1016/j.jri.2008.06.001] [PMID:  18715652] 
[57] 
Runz S, Keller S, Rupp C, et al. Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecol Oncol  2007; 107(3): 563-71.
[http://dx.doi.org/10.1016/j.ygyno.2007.08.064] [PMID:  17900673] 
[58] 
Levänen B, Bhakta NR, Paredes PT, et al. Altered microRNA
	profiles in bronchoalveolar lavage fluid exosomes in
	asthmatic patients J Allergy Clin Immunol 2013; 131(3): 894-
903 e8 
[59] 
Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget  2015; 6(35): 37043-53.
[http://dx.doi.org/10.18632/oncotarget.6158] [PMID:  26497684] 
[60] 
Masyuk AI, Huang BQ, Ward CJ, et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol  2010; 299(4): G990-9.
[http://dx.doi.org/10.1152/ajpgi.00093.2010] [PMID:  20634433] 
[61] 
Tian W, Liu S, Li B. Potential role of exosomes in cancer metastasis. BioMed Res Int  2019; •••104649705
[http://dx.doi.org/10.1155/2019/4649705] 
[62] 
Wan Z, Gao X, Dong Y, et al. Exosome-mediated cell-cell communication in tumor progression. Am J Cancer Res  2018; 8(9): 1661-73.
[PMID: 30323961] 
[63] 
Zhang Y, Liu D, Chen X, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell  2010; 39(1): 133-44.
[http://dx.doi.org/10.1016/j.molcel.2010.06.010] [PMID:  20603081] 
[64] 
Gottipamula S, Bhat S, Seetharam RN. Mesenchymal stromal cells: basics, classification, and clinical applications. J Stem Cells  2018; 13(1): 23-47.
[65] 
Marino L, Castaldi MA, Rosamilio R, et al. Mesenchymal stem cells from the Wharton’s jelly of the human umbilical cord: biological properties and therapeutic potential. Int Stem Cells  2019; 12(2): 218.
[PMID: 31648394] 
[66] 
Anand S, Samuel M, Kumar S, Mathivanan S. Ticket to a bubble ride: Cargo sorting into exosomes and extracellular vesicles. Biochim Biophys Acta Proteins Proteomics  2019; 1867(12)140203
[http://dx.doi.org/10.1016/j.bbapap.2019.02.005] [PMID:  30822540] 
[67] 
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science  2020; 367(6478)eaau6977
[http://dx.doi.org/10.1126/science.aau6977] [PMID:  32029601] 
[68] 
Lou G, Chen L, Xia C, et al. MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. J Exp Clin Cancer Res  2020; 39(1): 4.
[http://dx.doi.org/10.1186/s13046-019-1512-5] [PMID:  31898515] 
[69] 
Liang X, Zhang L, Wang S, Han Q, Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci  2016; 129(11): 2182-9.
[http://dx.doi.org/10.1242/jcs.170373] [PMID:  27252357] 
[70] 
Lin R, Wang S, Zhao RC. Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. Mol Cell Biochem  2013; 383(1-2): 13-20.
[http://dx.doi.org/10.1007/s11010-013-1746-z] [PMID:  23812844] 
[71] 
Xu JF, Yang GH, Pan XH, et al. Altered microRNA expression profile in exosomes during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. PLoS One  2014; 9(12)e114627
[http://dx.doi.org/10.1371/journal.pone.0114627] [PMID:  25503309] 
[72] 
Ding J, Wang X, Chen B, Zhang J, Xu J. Exosomes derived from human bone marrow mesenchymal stem cells stimulated by deferoxamine accelerate cutaneous wound healing by promoting angiogenesis. BioMed Res Int  2019; 20199742765
[http://dx.doi.org/10.1155/2019/9742765] [PMID:  31192260] 
[73] 
Xin H, Katakowski M, Wang F, et al. MicroRNA-17–92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke  2017; 48(3): 747-53.
[http://dx.doi.org/10.1161/STROKEAHA.116.015204] [PMID:  28232590] 
[74] 
Zhang Y, Chopp M, Liu XS, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol  2017; 54(4): 2659-73.
[http://dx.doi.org/10.1007/s12035-016-9851-0] [PMID:  26993303] 
[75] 
Xin H, Li Y, Buller B, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells  2012; 30(7): 1556-64.
[http://dx.doi.org/10.1002/stem.1129] [PMID:  22605481] 
[76] 
McBride JD, Rodriguez-Menocal L, Guzman W, Candanedo A, Garcia-Contreras M, Badiavas EV. Bone marrow mesenchymal stem cell-derived CD63+ exosomes transport Wnt3a exteriorly and enhance dermal fibroblast proliferation, migration, and angiogenesis in vitro. Stem Cells Dev  2017; 26(19): 1384-98.
[http://dx.doi.org/10.1089/scd.2017.0087] [PMID:  28679315] 
[77] 
Zhang B, Shen L, Shi H, et al. Exosomes from human umbilical cord mesenchymal stem cells: identification, purification, and biological characteristics. Stem Cells Int  2016; 20161929536
[http://dx.doi.org/10.1155/2016/1929536] 
[78] 
Shao M, Xu Q, Wu Z, et al. Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p. Stem Cell Res Ther  2020; 11(1): 37.
[http://dx.doi.org/10.1186/s13287-020-1550-0] [PMID:  31973730] 
[79] 
Sun L, Li D, Song K, et al. Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro. Sci Rep  2017; 7(1): 2552.
[http://dx.doi.org/10.1038/s41598-017-02786-x] [PMID:  28566720] 
[80] 
Tang Y, Zhang YC, Chen Y, Xiang Y, Shen CX, Li YG. The role of miR-19b in the inhibition of endothelial cell apoptosis and its relationship with coronary artery disease. Sci Rep  2015; 5: 15132.
[http://dx.doi.org/10.1038/srep15132] [PMID:  26459935] 
[81] 
Li X, Liu L, Yang J, et al. Exosome derived from human umbilical cord mesenchymal stem cell mediates MiR-181c attenuating burn-induced excessive inflammation. EBioMedicine  2016; 8: 72-82.
[http://dx.doi.org/10.1016/j.ebiom.2016.04.030] [PMID:  27428420] 
[82] 
Liu L, Yu Y, Hou Y, et al. Human umbilical cord mesenchymal stem cells transplantation promotes cutaneous wound healing of severe burned rats. PLoS One  2014; 9(2)e88348
[http://dx.doi.org/10.1371/journal.pone.0088348] [PMID:  24586314] 
[83] 
Tavakoli Dargani Z, Singla DK. Embryonic stem cell-derived exosomes inhibit doxorubicin-induced TLR4-NLRP3-mediated cell death-pyroptosis. Am J Physiol Heart Circ Physiol  2019; 317(2): H460-71.
[http://dx.doi.org/10.1152/ajpheart.00056.2019] [PMID:  31172809] 
[84] 
Chen B, Sun Y, Zhang J, et al. Human embryonic stem cell-derived exosomes promote pressure ulcer healing in aged mice by rejuvenating senescent endothelial cells. Stem Cell Res Ther  2019; 10(1): 1-17.
[http://dx.doi.org/10.1186/s13287-018-1105-9] [PMID:  30606242] 
[85] 
Zhang S, Chu WC, Lai RC, Lim SK, Hui JH, Toh WS. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage  2016; 24(12): 2135-40.
[http://dx.doi.org/10.1016/j.joca.2016.06.022] [PMID:  27390028] 
[86] 
Zhang S, Chuah SJ, Lai RC, et al. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials 2018; 156: 16-27. Biomaterials  2018; 156: 16-27.
[http://dx.doi.org/10.1016/j.biomaterials.2017.11.028] [PMID:  29182933] 
[87] 
Zhang J, Chen C, Hu B, et al. Exosomes derived from human endothelial progenitor cells accelerate cutaneous wound healing by promoting angiogenesis through Erk1/2 signaling. Int J Biol Sci  2016; 12(12): 1472-87.
[http://dx.doi.org/10.7150/ijbs.15514] [PMID:  27994512] 
[88] 
Kim S, Lee SK, Kim H, Kim TM. Exosomes secreted from induced pluripotent stem cell-derived mesenchymal stem cells accelerate skin cell proliferation. Int J Mol Sci  2018; 19(10): 3119.
[http://dx.doi.org/10.3390/ijms19103119] [PMID:  30314356] 
[89] 
Du Y, Li D, Han C, et al. Exosomes from human-induced pluripotent stem cell–derived mesenchymal stromal cells (hiPSC-MSCs) protect liver against hepatic ischemia/reperfusion injury via activating sphingosine kinase and sphingosine-1-phosphate signaling pathway. Cell Physiol Biochem  2017; 43(2): 611-25.
[http://dx.doi.org/10.1159/000480533] [PMID:  28934733] 
[90] 
Qin W, Tsukasaki Y, Dasgupta S, Mukhopadhyay N, Ikebe M, Sauter ER. Exosomes in human breast milk promote EMT. Clin Cancer Res  2016; 22(17): 4517-24.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0135] [PMID:  27060153] 
[91] 
Mirza AH, Kaur S, Nielsen LB, et al. Breast milk-derived extracellular vesicles enriched in exosomes from mothers with type 1 diabetes contain aberrant levels of microRNAs. Front Immunol  2019; 10: 2543.
[http://dx.doi.org/10.3389/fimmu.2019.02543] [PMID:  31708933] 
[92] 
Gildea JJ, Carlson JM, Schoeffel CD, Carey RM, Felder RA. Urinary exosome miRNome analysis and its applications to salt sensitivity of blood pressure. Clin Biochem  2013; 46(12): 1131-4.
[http://dx.doi.org/10.1016/j.clinbiochem.2013.05.052] [PMID:  23726803] 
[93] 
Jiang A, Zhang S, Li Z, et al. miR-615-3p promotes the phagocytic capacity of splenic macrophages by targeting ligand-dependent nuclear receptor corepressor in cirrhosis-related portal hypertension. Exp Biol Med (Maywood)  2011; 236(6): 672-80.
[http://dx.doi.org/10.1258/ebm.2011.010349] [PMID:  21565892] 
[94] 
Teixeira AL, Gomes M, Medeiros R. EGFR signaling pathway and related-miRNAs in age-related diseases: the example of miR-221 and miR-222. Front Genet  2012; 3: 286.
[http://dx.doi.org/10.3389/fgene.2012.00286] [PMID:  23233863] 
[95] 
Yang T, Liang Y, Lin Q, et al. miR-29 mediates TGFβ1-induced extracellular matrix synthesis through activation of PI3K-AKT pathway in human lung fibroblasts. J Cell Biochem  2013; 114(6): 1336-42.
[http://dx.doi.org/10.1002/jcb.24474] [PMID:  23238947] 
[96] 
Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A, Fraser D. Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol  2010; 21(3): 438-47.
[http://dx.doi.org/10.1681/ASN.2009050530] [PMID:  20056746] 
[97] 
Hiemstra TF, Charles PD, Gracia T, et al. Human urinary exosomes as innate immune effectors. J Am Soc Nephrol  2014; 25(9): 2017-27.
[http://dx.doi.org/10.1681/ASN.2013101066] [PMID:  24700864] 
[98] 
Weeraratne SD, Amani V, Teider N, et al. Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma. Acta Neuropathol  2012; 123(4): 539-52.
[http://dx.doi.org/10.1007/s00401-012-0969-5] [PMID:  22402744] 
[99] 
Li M, Zeringer E, Barta T, Schageman J, Cheng A, Vlassov AV. Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. Philos Trans R Soc Lond B Biol Sci  2014; 369(1652)20130502
[http://dx.doi.org/10.1098/rstb.2013.0502] [PMID:  25135963] 
[100] 
Lin Q, Mao W, Shu Y, et al. A cluster of specified microRNAs in peripheral blood as biomarkers for metastatic non-small-cell lung cancer by stem-loop RT-PCR. J Cancer Res Clin Oncol  2012; 138(1): 85-93.
[http://dx.doi.org/10.1007/s00432-011-1068-z] [PMID:  22009180] 
[101] 
Ji Q, Ji Y, Peng J, et al. Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients. PLoS One  2016; 11(9)e0163645
[http://dx.doi.org/10.1371/journal.pone.0163645] [PMID:  27661079] 
[102] 
Bi S, Wang C, Jin Y, Lv Z, Xing X, Lu Q. Correlation between serum exosome derived miR-208a and acute coronary syndrome. Int J Clin Exp Med  2015; 8(3): 4275-80.
[PMID: 26064341] 
[103] 
Ju S, Mu J, Dokland T, et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol Ther  2013; 21(7): 1345-57.
[http://dx.doi.org/10.1038/mt.2013.64] [PMID:  23752315] 
[104] 
Zhuang X, Deng ZB, Mu J, et al. Ginger-derived nanoparticles protect against alcohol-induced liver damage. J Extracell Vesicles  2015; 4(1): 28713.
[http://dx.doi.org/10.3402/jev.v4.28713] [PMID:  26610593] 
[105] 
Chen X, Zhou Y, Yu J. Exosome-like nanoparticles from ginger rhizomes inhibited NLRP3 inflammasome activation. Mol Pharm  2019; 16(6): 2690-9.
[http://dx.doi.org/10.1021/acs.molpharmaceut.9b00246] [PMID:  31038962] 
[106] 
Raimondo S, Naselli F, Fontana S, et al. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death. Oncotarget  2015; 6(23): 19514-27.
[http://dx.doi.org/10.18632/oncotarget.4004] [PMID:  26098775] 
[107] 
Deng Z, Rong Y, Teng Y, et al. Broccoli-derived nanoparticle inhibits mouse colitis by activating dendritic cell AMP-activated protein kinase. Mol Ther  2017; 25(7): 1641-54.
[http://dx.doi.org/10.1016/j.ymthe.2017.01.025] [PMID:  28274798] 
[108] 
Takeo M, Lee W, Ito M. Wound healing and skin regeneration. Cold Spring Harb Perspect Med  2015; 5(1)a023267
[http://dx.doi.org/10.1101/cshperspect.a023267] [PMID:  25561722] 
[109] 
Pathak MA, Nghiem P, Fitzpatrick TB. Acute and chronic effects of the sunFitzpatricks Dermatology in General Medicine.  New York: Mc-Graw Hill 1999; pp. 1598-606.
[110] 
Taylor SC. Skin of color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol  2002; 46(2): S41-62.
[111] 
Rawlings AV. Ethnic skin types: are there differences in skin structure and function? Int J Cosmet Sci  2006; 28(2): 79-93.
[http://dx.doi.org/10.1111/j.1467-2494.2006.00302.x] [PMID:  18492142] 
[112] 
Chuong CM, Nickoloff BJ, Elias PM, et al. What is the ‘true’ function of skin? Exp Dermatol  2002; 11(2): 159-87.
[PMID: 11994143] 
[113] 
Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res  2009; 37(5): 1528-42.
[http://dx.doi.org/10.1177/147323000903700531] [PMID:  19930861] 
[114] 
Singh S, Young A, McNaught CE. The physiology of wound healing. Surgery  2017; 35(9): 473-7.
[115] 
Caley MP, Martins VL, O’Toole EA. Metalloproteinases and wound healing. Adv Wound Care (New Rochelle)  2015; 4(4): 225-34.
[http://dx.doi.org/10.1089/wound.2014.0581] [PMID:  25945285] 
[116] 
A yuk SM, Abrahamse H, Houreld NN. The role of matrix metalloproteinases in diabetic wound healing in relation to photobiomodulation. J Diabetes Res  2016; 20162897656
[117] 
Sabino F, Auf dem Keller U. Matrix metalloproteinases in impaired wound healing. Metalloproteinases Med  2015; 2: 1-8.
[118] 
Cornelius LA, Nehring LC, Harding E, et al. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol  1998; 161(12): 6845-52.
[PMID: 9862716] 
[119] 
Sudbeck BD, Pilcher BK, Welgus HG, Parks WC. Induction and repression of collagenase-1 by keratinocytes is controlled by distinct components of different extracellular matrix compartments. J Biol Chem  1997; 272(35): 22103-10.
[http://dx.doi.org/10.1074/jbc.272.35.22103] [PMID:  9268353] 
[120] 
Hattori N, Mochizuki S, Kishi K, et al. MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing. Am J Pathol  2009; 175(2): 533-46.
[http://dx.doi.org/10.2353/ajpath.2009.081080] [PMID:  19590036] 
[121] 
Armstrong DG, Jude EB. The role of matrix metalloproteinases in wound healing. J Am Podiatr Med Assoc  2002; 92(1): 12-8.
[http://dx.doi.org/10.7547/87507315-92-1-12] [PMID:  11796794] 
[122] 
Stadelmann WK, Digenis AG, Tobin GR. Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg  1998; 176(Suppl. 2A): 26S-38S.
[http://dx.doi.org/10.1016/S0002-9610(98)00183-4] [PMID:  9777970] 
[123] 
O’Toole EA. Extracellular matrix and keratinocyte migration. Clin Exp Dermatol  2001; 26(6): 525-30.
[http://dx.doi.org/10.1046/j.1365-2230.2001.00891.x] [PMID:  11678882] 
[124] 
Widgerow AD. Chronic wound fluid--thinking outside the box. Wound Repair Regen  2011; 19(3): 287-91.
[http://dx.doi.org/10.1111/j.1524-475X.2011.00683.x] [PMID:  21518088] 
[125] 
Thiruvoth FM, Mohapatra DP, Sivakumar DK, et al. Current concepts in the physiology of adult wound healing. Plast Aesthet Res  2015; 2(5): 250-6.
[http://dx.doi.org/10.4103/2347-9264.158851] 
[126] 
Gosain A, DiPietro LA. Aging and wound healing. World J Surg  2004; 28(3): 321-6.
[http://dx.doi.org/10.1007/s00268-003-7397-6] [PMID:  14961191] 
[127] 
Broughton GII, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg  2006; 117(Suppl. 7): 12S-34S.
[http://dx.doi.org/10.1097/01.prs.0000225430.42531.c2] [PMID:  16799372] 
[128] 
Campos AC, Groth AK, Branco AB. Assessment and nutritional aspects of wound healing. Curr Opin Clin Nutr Metab Care  2008; 11(3): 281-8.
[http://dx.doi.org/10.1097/MCO.0b013e3282fbd35a] [PMID:  18403925] 
[129] 
Meszaros AJ, Reichner JS, Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol  2000; 165(1): 435-41.
[http://dx.doi.org/10.4049/jimmunol.165.1.435] 
[130] 
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nature reviews immunology  2008; 8(12): 958-69.
[http://dx.doi.org/10.1038/nri2448] [PMID:  19029990] 
[131] 
Krishnaswamy VR, Mintz D, Sagi I. Matrix metalloproteinases: The sculptors of chronic cutaneous wounds. Biochim Biophys Acta Mol Cell Res  2017; 1864(11 Pt B): 2220-7.
[http://dx.doi.org/10.1016/j.bbamcr.2017.08.003] [PMID:  28797647] 
[132] 
Vaalamo M, Mattila L, Johansson N, et al. Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol  1997; 109(1): 96-101.
[http://dx.doi.org/10.1111/1523-1747.ep12276722] [PMID:  9204962] 
[133] 
Barone EJ, Yager DR, Pozez AL, et al. Interleukin-1alpha and collagenase activity are elevated in chronic wounds. Plast Reconstr Surg  1998; 102(4): 1023-7.
[http://dx.doi.org/10.1097/00006534-199809020-00015] [PMID:  9734419] 
[134] 
Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle)  2015; 4(9): 560-82.
[http://dx.doi.org/10.1089/wound.2015.0635] [PMID:  26339534] 
[135] 
Mathieu D, Linke JC, Wattel F. Non-healing wounds Handbook on hyperbaric medicine.  Dordrecht: Springer 2006; pp. 401-28.
[http://dx.doi.org/10.1007/1-4020-4448-8_20] 
[136] 
Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol  2007; 25(1): 19-25.
[http://dx.doi.org/10.1016/j.clindermatol.2006.12.005] [PMID:  17276197] 
[137] 
Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract  2017; 128: 40-50.
[http://dx.doi.org/10.1016/j.diabres.2017.03.024] [PMID:  28437734] 
[138] 
Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol  2001; 117(5): 1027-35.
[http://dx.doi.org/10.1046/j.0022-202x.2001.01539.x] [PMID:  11710909] 
[139] 
Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg  2004; 187(5A): 11S-6S.
[http://dx.doi.org/10.1016/S0002-9610(03)00296-4] [PMID:  15147986] 
[140] 
Gawronska-Kozak B, Bogacki M, Rim JS, Monroe WT, Manuel JA. Scarless skin repair in immunodeficient mice. Wound Repair Regen  2006; 14(3): 265-76.
[http://dx.doi.org/10.1111/j.1743-6109.2006.00121.x] [PMID:  16808805] 
[141] 
Jameson J, Havran WL. Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol Rev  2007; 215(1): 114-22.
[http://dx.doi.org/10.1111/j.1600-065X.2006.00483.x] [PMID:  17291283] 
[142] 
Mills RE, Taylor KR, Podshivalova K, McKay DB, Jameson JM. Defects in skin γ δ T cell function contribute to delayed wound repair in rapamycin-treated mice. J Immunol  2008; 181(6): 3974-83.
[http://dx.doi.org/10.4049/jimmunol.181.6.3974] [PMID:  18768852] 
[143] 
Rennert RC, Rodrigues M, Wong VW, et al. Biological therapies for the treatment of cutaneous wounds: phase III and launched therapies. Expert Opin Biol Ther  2013; 13(11): 1523-41.
[http://dx.doi.org/10.1517/14712598.2013.842972] [PMID:  24093722] 
[144] 
Vyas KS, Vasconez HC. Wound healing: biologics, skin substitutes, biomembranes and scaffolds. Healthcare (Basel)  2014; 2(3): 356-400.
[http://dx.doi.org/10.3390/healthcare2030356] [PMID:  27429283] 
[145] 
Donnelly H, Dalby MJ, Salmeron-Sanchez M, Sweeten PE. Current approaches for modulation of the nanoscale interface in the regulation of cell behavior. Nanomedicine (Lond)  2018; 14(7): 2455-64.
[http://dx.doi.org/10.1016/j.nano.2017.03.020] [PMID:  28552647] 
[146] 
Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep  2015; 35(2)e00191
[http://dx.doi.org/10.1042/BSR20150025] [PMID:  25797907] 
[147] 
Yang R, Liu F, Wang J, Chen X, Xie J, Xiong K. Epidermal stem cells in wound healing and their clinical applications. Stem Cell Res Ther  2019; 10(1): 229.
[http://dx.doi.org/10.1186/s13287-019-1312-z] [PMID:  31358069] 
[148] 
Wu Y, Wang J, Scott PG, Tredget EE. Bone marrow-derived stem cells in wound healing: a review. Wound Repair Regen  2007; 15(Suppl. 1): S18-26.
[http://dx.doi.org/10.1111/j.1524-475X.2007.00221.x] [PMID:  17727462] 
[149] 
Liu ZJ, Velazquez OC. Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing. Antioxid Redox Signal  2008; 10(11): 1869-82.
[http://dx.doi.org/10.1089/ars.2008.2121] [PMID:  18627349] 
[150] 
Rea S, Giles NL, Webb S, et al. Bone marrow-derived cells in the healing burn wound--more than just inflammation. Burns  2009; 35(3): 356-64.
[http://dx.doi.org/10.1016/j.burns.2008.07.011] [PMID:  18952376] 
[151] 
Kørbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept? N Engl J Med  2003; 349(6): 570-82.
[http://dx.doi.org/10.1056/NEJMra022361] [PMID:  12904523] 
[152] 
Al-Shaibani MBH, Wang XN, Lovat PE, et al. Cellular therapy for wounds: applications of mesenchymal stem cells in wound healing Wound Healing—New insights into ancient challenges. Rijeka, Croatia: InTech 2016.
[http://dx.doi.org/10.5772/63963] 
[153] 
Bartosh TJ, Ylöstalo JH, Mohammadipoor A, et al. Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci USA  2010; 107(31): 13724-9.
[http://dx.doi.org/10.1073/pnas.1008117107] [PMID:  20643923] 
[154] 
Rustad KC, Wong VW, Sorkin M, et al. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials  2012; 33(1): 80-90.
[http://dx.doi.org/10.1016/j.biomaterials.2011.09.041] [PMID:  21963148] 
[155] 
Ko SH, Nauta A, Wong V, Glotzbach J, Gurtner GC, Longaker MT. The role of stem cells in cutaneous wound healing: what do we really know? Plast Reconstr Surg  2011; 127(Suppl. 1): 10S-20S.
[http://dx.doi.org/10.1097/PRS.0b013e3181fbe2d8] [PMID:  21200267] 
[156] 
Roh C, Lyle S. Cutaneous stem cells and wound healing. Pediatr Res  2006; 59(4 Pt 2): 100R-3R.
[http://dx.doi.org/10.1203/01.pdr.0000203572.51876.ba] [PMID:  16549556] 
[157] 
Meyerrose TE, De Ugarte DA, Hofling AA, et al. In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells  2007; 25(1): 220-7.
[http://dx.doi.org/10.1634/stemcells.2006-0243] [PMID:  16960135] 
[158] 
Katsuda T, Tsuchiya R, Kosaka N, et al. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep  2013; 3: 1197.
[http://dx.doi.org/10.1038/srep01197] [PMID:  23378928] 
[159] 
Choi EW, Seo MK, Woo EY, Kim SH, Park EJ, Kim S. Exosomes from human adipose-derived stem cells promote proliferation and migration of skin fibroblasts. Exp Dermatol  2018; 27(10): 1170-2.
[http://dx.doi.org/10.1111/exd.13451] [PMID:  28940813] 
[160] 
Roşca AM, Ţuţuianu R, Titorencu ID. Mesenchymal stromal cells derived exosomes as tools for chronic wound healing therapy. Rom J Morphol Embryol  2018; 59(3): 655-62.
[PMID: 30534802] 
[161] 
Ong SG, Wu JC. Exosomes as potential alternatives to stem cell therapy in mediating cardiac regeneration. Circ Res  2015; 117(1): 7-9.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306593] [PMID:  26089361] 
[162] 
Golchin A, Hosseinzadeh S, Ardeshirylajimi A. The exosomes released from different cell types and their effects in wound healing. J Cell Biochem  2018; 119(7): 5043-52.
[http://dx.doi.org/10.1002/jcb.26706] [PMID:  29377240] 
[163] 
Li M, Wang T, Tian H, Wei G, Zhao L, Shi Y. Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model. Artif Cells Nanomed Biotechnol  2019; 47(1): 3793-803.
[http://dx.doi.org/10.1080/21691401.2019.1669617] [PMID:  31556314] 
[164] 
Anderson JD, Johansson HJ, Graham CS, et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor‐kappaB signaling. Stem Cells  2016; 34(3): 601-13.
[http://dx.doi.org/10.1002/stem.2298] [PMID:  26782178] 
[165] 
Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E. 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.
[http://dx.doi.org/10.1089/scd.2014.0316] [PMID:  25867197] 
[166] 
Consortium GO. The Gene Ontology (GO) database and informatics resource. Acids Res  2004; 32(1): D258-61.
[167] 
Ogata H, Goto S, Sato K, Fujibuchi W, Bono H, Kanehisa M. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res  1999; 27(1): 29-34.
[http://dx.doi.org/10.1093/nar/27.1.29] [PMID:  9847135] 
[168] 
Kanehisa M. Post-genome informatics. Oxford, UK: Oxford University Press 2000.
[169] 
Kanehisa M. A database for post-genome analysis. Trends Genet  1997; 13(9): 375-6.
[http://dx.doi.org/10.1016/S0168-9525(97)01223-7] [PMID:  9287494] 
[170] 
Goto S, Nishioka T, Kanehisa M. LIGAND: chemical database of enzyme reactions. Nucleic Acids Res  2000; 28(1): 380-2.
[http://dx.doi.org/10.1093/nar/28.1.380] [PMID:  10592281] 
[171] 
Xiong J, Liu Z, Wu M, et al. Comparison of proangiogenic effects of adipose-derived stem cells and foreskin fibroblast exosomes on artificial dermis prefabricated flapsStem Cells
	Int 2020; 2020: ID 5293850 
[http://dx.doi.org/10.1155/2020/5293850] 
[172] 
Zhang S, Yang Y, Jia S, et al. Exosome-like vesicles derived from Hertwig’s epithelial root sheath cells promote the regeneration of dentin-pulp tissue. Theranostics  2020; 10(13): 5914-31.
[http://dx.doi.org/10.7150/thno.43156] [PMID:  32483427] 
[173] 
Dennis G Jr, Sherman BT, Hosack DA, et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol  2003; 4(5): 3.
[http://dx.doi.org/10.1186/gb-2003-4-5-p3] [PMID:  12734009] 
[174] 
Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc  2009; 4(1): 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID:  19131956] 
[175] 
Ren S, Chen J, Duscher D, et al. Microvesicles from human adipose stem cells promote wound healing by optimizing cellular functions via AKT and ERK signaling pathways. Stem Cell Res Ther  2019; 10(1): 47.
[http://dx.doi.org/10.1186/s13287-019-1152-x] [PMID:  30704535] 
[176] 
Choi JS, Cho WL, Choi YJ, et al. Functional recovery in photo-damaged human dermal fibroblasts by human adipose-derived stem cell extracellular vesicles. J Extracell Vesicles  2019; 8(1)1565885
[http://dx.doi.org/10.1080/20013078.2019.1565885] [PMID:  30719241] 
[177] 
Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res  2015; 43(Database issue): D447-52.
[http://dx.doi.org/10.1093/nar/gku1003] [PMID:  25352553] 
[178] 
Karimizadeh E, Sharifi-Zarchi A, Nikaein H, et al. Analysis of gene expression profiles and protein-protein interaction networks in multiple tissues of systemic sclerosis. BMC Med Genomics  2019; 12(1): 199.
[http://dx.doi.org/10.1186/s12920-019-0632-2] [PMID:  31881890] 
[179] 
Valencia A, Pazos F. Computational methods for the prediction of protein interactions. Curr Opin Struct Biol  2002; 12(3): 368-73.
[http://dx.doi.org/10.1016/S0959-440X(02)00333-0] [PMID:  12127457] 
[180] 
Huynen MA, Snel B, von Mering C, Bork P. Function prediction and protein networks. Curr Opin Cell Biol  2003; 15(2): 191-8.
[http://dx.doi.org/10.1016/S0955-0674(03)00009-7] [PMID:  12648675] 
[181] 
Lewis AC, Saeed R, Deane CM. Predicting protein-protein interactions in the context of protein evolution. Mol Biosyst  2010; 6(1): 55-64.
[http://dx.doi.org/10.1039/B916371A] [PMID:  20024067] 
[182] 
Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M. Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res  2014; 42(Database issue): D199-205.
[http://dx.doi.org/10.1093/nar/gkt1076] [PMID:  24214961] 
[183] 
Hornick NI, Doron B, Abdelhamed S, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal  2016; 9(444): ra88-.
[http://dx.doi.org/10.1126/scisignal.aaf2797] [PMID:  27601730] 
[184] 
Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal stem cell‐derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med  2016; 5(12): 1620-30.
[http://dx.doi.org/10.5966/sctm.2015-0285] [PMID:  27460850] 
[185] 
Comley J. Pathway analysis.  Drug Discovery 2012; p. 41.
[186] 
Migneault F, Dieudé M, Turgeon J, et al. Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway. Sci Rep  2020; 10(1): 1-15.
[http://dx.doi.org/10.1038/s41598-020-69548-0] [PMID:  31913322] 
[187] 
Zhou Y, Yamamoto Y, Xiao Z, Ochiya T. The immunomodulatory functions of mesenchymal stromal/stem cells mediated via paracrine activity. J Clin Med  2019; 8(7): 1025.
[http://dx.doi.org/10.3390/jcm8071025] [PMID:  31336889] 
[188] 
De Robertis M, Sarra A, D’Oria V, et al. Blueberry-derived exosome-like nanoparticles counter the response to TNF-α-induced change on gene expression in EA. hy926 cells. Biomolecules  2020; 10(5): 742.
[http://dx.doi.org/10.3390/biom10050742] [PMID:  32397678] 
[189] 
Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics  2011; 27(3): 431-2.
[http://dx.doi.org/10.1093/bioinformatics/btq675] [PMID:  21149340] 
[190] 
Guo X, Ji J, Feng Z, Hou X, Luo Y, Mei Z. A network pharmacology approach to explore the potential targets underlying the effect of sinomenine on rheumatoid arthritis. Int Immunopharmacol  2020; 80106201
[http://dx.doi.org/10.1016/j.intimp.2020.106201] [PMID:  31972421] 
[191] 
Ferguson SW, Wang J, Lee CJ, et al. The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Rep  2018; 8(1): 1419.
[http://dx.doi.org/10.1038/s41598-018-19581-x] [PMID:  29362496] 
[192] 
Marco-Puche G, Lois S, Benítez J, Trivino JC. RNA-Seq perspectives to improve clinical diagnosis. Front Genet  2019; 10: 1152.
[http://dx.doi.org/10.3389/fgene.2019.01152] [PMID:  31781178] 
[193] 
Combs PA, Eisen MB. Low-cost, low-input RNA-seq protocols perform nearly as well as high-input protocols. PeerJ  2015; 3e869
[http://dx.doi.org/10.7717/peerj.869] [PMID:  25834775] 
[194] 
Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem  2008; 104(5): 1145-66.
[http://dx.doi.org/10.1111/j.1471-4159.2007.05099.x] [PMID:  17973979] 
Cite As
Current Molecular Medicine

Wound Healing Properties of Exosomes — A Review and Modelling of Combinatorial Analysis Strategies

Abstract
