Applications of mesenchymal stem cell-exosome components in wound infection healing: new insights

Abstract

The healing process at a wound is made up of many types of cells, growth factors, the extracellular matrix, nerves and blood vessels all interacting with each other in complex and changing ways. Microbial colonization and proliferation are possible at the place of injury, which makes infection more likely. Because of this, any cut has a chance of getting an infection. Researchers have found that wound infections make patients more upset and cost the healthcare system a lot of money. Surgical site infections happen a lot to people who have recently had surgery. This study shows that such surgical infection is linked to a high rate of illness and death. This is shown by the fact that 25% of patients get serious sepsis and need to be transferred to an intensive care unit. In both animal models and people, mesenchymal stem cells (MSCs) play an active role in all stages of wound healing and have positive effects. Exosomes are one of the main things MSCs release. They have effects that are similar to those of the parent MSCs. Various effector proteins, messenger RNA and microRNAs can be transported by extracellular vesicles to control the activity of target cells. This has a big impact on the healing process. These results suggest that using MSC-exosomes as a new type of cell-free therapy could be a better and safer option than whole cell therapy. This review is mostly about how to use parts of MSC-exosomes to help wound infections heal.

Keywords

Mesenchymal stem cells / Exosome component / mesenchymal stem cell-exosome / Wound / Wound healing / Wound infection

References

[1] Gan J, Zhang X, Ma W, Zhao Y, Sun L. Antibacterial, adhesive, and MSC exosomes encapsulated microneedles with spatiotemporal variation functions for diabetic wound healing. Nano Today. 2022; 47: 101630.

[2] Liu W, Yu M, Xie D, Wang L, Ye C, Zhu Q, et al. Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Res Ther. 2020; 11: 1-15.

[3] Marofi F, Alexandrovna KI, Margiana R, Bahramali M, Suksatan W, Abdelbasset WK, et al. MSCs and their exosomes: a rapidly evolving approach in the context of cutaneous wounds therapy. Stem Cell Res Ther. 2021; 12: 1-20.

[4] Lee B-C, Kang I, Yu K-R. Therapeutic features and updated clinical trials of mesenchymal stem cell (MSC)-derived exosomes. J Clin Med. 2021; 10: 711.

[5] Chinnadurai R, Forsberg MH, Kink JA, Hematti P, Capitini CM. Use of MSCs and MSC-educated macrophages to mitigate hematopoietic acute radiation syndrome. Curr Stem Cell Rep. 2020; 6: 77-85.

[6] Li C, An Y, Sun Y, Yang F, Xu Q, Wang Z. Adipose mesenchymal stem cell-derived exosomes promote wound healing through the WNT/β-catenin Signaling pathway in dermal fibroblasts. Stem Cell Rev Rep. 2022; 18: 2059-73.

[7] Magdy Beshbishy A, Alghamdi S, Onyiche TE, Zahoor M, Rivero-Perez N, Zaragoza-Bastida A, et al. Biogenesis, biologic function and clinical potential of exosomes in different diseases. Appl Sci. 2020; 10: 4428.

[8] Golchin A, Shams F, Basiri A, Ranjbarvan P, Kiani S, Sarkhosh-Inanlou R, et al. Combination therapy of stem cell-derived exosomes and biomaterials in the wound healing. Stem Cell Rev Rep. 2022; 18: 1892-911.

[9] Shi H, Wang M, Sun Y, Yang D, Xu W, Qian H. Exosomes: emerging cell-free based therapeutics in dermatologic diseases. Frontiers in Cell and Developmental Biology. 2021; 9: 736022.

[10] Raghav A, Khan ZA, Upadhayay VK, Tripathi P, Gautam KA, Mishra BK, et al. Mesenchymal stem cell-derived exosomes exhibit promising potential for treating SARS-CoV-2-infected patients. Cells. 2021; 10: 587.

[11] Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020; 18: 1-21.

[12] Shen M, Chen T. Mesenchymal stem cell-derived exosomes and their potential agents in hematological diseases. Oxidative Med Cell Longev. 2021; 2021: 1-13.

[13] Asadi K, Amini A, Gholami A. Mesenchymal stem cell-derived exosomes as a bioinspired nanoscale tool toward next-generation cell-free treatment. Journal of Drug Delivery Science and Technology. 2022; 77: 103856.

[14] Hu J-C, Zheng C-X, Sui B-D, Liu W-J, Jin Y. Mesenchymal stem cell-derived exosomes: a novel and potential remedy for cutaneous wound healing and regeneration. World Journal of Stem Cells. 2022; 14: 318-29.

[15] Hu P, Yang Q, Wang Q, Shi C, Wang D, Armato U, et al. Mesenchymal stromal cells-exosomes: a promising cell-free therapeutic tool for wound healing and cutaneous regeneration. Burns & trauma. 2019; 7: 7.

[16] Zhao W, Zhang H, Liu R, Cui R. Advances in immunomodulatory mechanisms of mesenchymal stem cells-derived exosome on immune cells in scar formation. Int J Nanomedicine. 2023; 18: 3643-62.

[17] 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: 1635-47.

[18] Prasai A, Jay JW, Jupiter D, Wolf SE, El Ayadi A. Role of exosomes in dermal wound healing: a systematic review. The Journal of investigative dermatology. 2022; 142: 662-678.e8.

[19] Xu H-K, Chen L-J, Zhou S-N, Li Y-F, Xiang C. Multifunctional role of microRNAs in mesenchymal stem cell-derived exosomes in treatment of diseases. World Journal of Stem Cells. 2020; 12: 1276-94.

[20] Fayazi N, Sheykhhasan M, Soleimani Asl S, Najafi R. Stem cell-derived exosomes: a new strategy of neurodegenerative disease treatment. Mol Neurobiol. 2021; 58: 3494-514.

[21] Riau AK, Ong HS, Yam GH, Mehta JS. Sustained delivery system for stem cell-derived exosomes. Front Pharmacol. 2019; 10: 1368.

[22] Li T, Li X, Han G, Liang M, Yang Z, Zhang C, et al. The therapeutic potential and clinical significance of exosomes as carriers of drug delivery system. Pharmaceutics. 2022; 15: 21.

[23] Huang J, Zhang J, Xiong J, Sun S, Xia J, Yang L, et al. Stem cell-derived nanovesicles: a novel cell-free therapy for wound healing. Stem Cells Int. 2021; 2021: 1-14.

[24] Knight R, Board-Davies E, Brown H, Clayton A, Davis T, Karatas B, et al. Oral progenitor cell line-derived small extracellular vesicles as a treatment for preferential wound healing outcome. Stem Cells Transl Med. 2022; 11: 861-75.

[25] Mirshekar M, Afkhami H, Razavi S, Jazi FM, Darban-Sarokhalil D, Ohadi E, et al. Potential antibacterial activity and healing effect of topical administration of bone marrow and adipose mesenchymal stem cells encapsulated in collagen-fibrin hydrogel scaffold on full-thickness burn wound infection caused by Pseudomonas aeruginosa. Burns (Elsevier journal). 2023; 49: 1944-57.

[26] Wang J, Zhang D, Zhu Y, Mo X, McHugh PC, Tong Q. Astragalus and human mesenchymal stem cells promote wound healing by mediating immunomodulatory effects through paracrine signaling. Regen Med. 2022; 17: 219-32.

[27] Khan SU, Khan MI, Khan MU, Khan NM, Bungau S, Hassan SS. Applications of extracellular vesicles in nervous system disorders: An overview of recent advances. Bioengineering. 2022; 10.

[28] Caldwell MD.Bacteria and antibiotics in wound healing. Surgical Clinics. 2020; 100: 757-76.

[29] Toppino S, Koffi DY, Kone BV, N’Krumah RT, Coulibaly ID, Tobian F, et al. Community-based wound management in a rural setting of Côte d’Ivoire. PLoS Negl Trop Dis. 2022; 16: e0010730.

[30] Aljghami ME, Saboor S, Amini-Nik S. Emerging innovative wound dressings. Ann Biomed Eng. 2019; 47: 659-75.

[31] Lei J, Sun L, Li P, Zhu C, Lin Z, Mackey V, et al. The wound dressings and their applications in wound healing and management. Health Sci J. 2019; 13: 1-8.

[32] Bowers S, Franco E. Chronic wounds: evaluation and management. Am Fam Physician. 2020; 101: 159-66.

[33] Tomic-Canic M, Burgess JL, O’Neill KE, Strbo N, Pastar I. Skin microbiota and its interplay with wound healing. Am J Clin Dermatol. 2020; 21: 36-43.

[34] Bacci S. Fine regulation during wound healing by mast cells, a physiological role not yet clarified. Int J Mol Sci. 2022; 23: 1820.

[35] Mahmoudvand G, Karimi Rouzbahani A, Razavi ZS, Mahjoor M, Afkhami H. Afkhami HJFib, biotechnology. Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: new insight. 2023; 11: 1158484.

[36] Kuang L, Zhang C, Li B, Deng H, Chen R, Li G. Human keratinocyte-derived Exosomal MALAT1 promotes diabetic wound healing by upregulating MFGE8 via microRNA-1914-3p. Int J Nanomedicine. 2023;Volume 18: 949-70.

[37] Riedl J, Popp C, Eide C, Ebens C, Tolar J. Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment. Cytotherapy. 2021; 23: 961-73.

[38] Liang Y, He J, Guo B. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano. 2021; 15: 12687-722.

[39] Tian M-P, Zhang A-D, Yao Y-X, Chen X-G, Liu Y. Mussel-inspired adhesive and polypeptide-based antibacterial thermo-sensitive hydroxybutyl chitosan hydrogel as BMSCs 3D culture matrix for wound healing. Carbohydr Polym. 2021; 261: 117878.

[40] Mahjoor M, Fakouri A, Farokhi S, Nazari H, Afkhami H, Heidari F. Regenerative potential of mesenchymal stromal cells in wound healing: unveiling the influence of normoxic and hypoxic environments. Front Cell Dev Biol. 2023; 11: 1245872.

[41] Abdul Kareem N, Aijaz A, Jeschke MG. Stem cell therapy for burns: story so far, Vol. Volume 15. Biologics: Targets and Therapy, 2021, 379-97.

[42] Yin K, Wang S, Zhao RC. Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark Res. 2019; 7: 1-8.

[43] Zhang S, Teo KYW, Chuah SJ, Lai RC, Lim SK, Toh WS. MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials. 2019; 200: 35-47.

[44] Chen S, Sun F, Qian H, Xu W, Jiang J. Preconditioning and engineering strategies for improving the efficacy of mesenchymal stem cell-derived exosomes in cell-free therapy. Stem Cells Int. 2022; 2022: 1-18.

[45] Dong R, Liu Y, Yang Y, Wang H, Xu Y, Zhang Z. MSC-derived exosomes-based therapy for peripheral nerve injury: a novel therapeutic strategy. Biomed Res Int. 2019; 2019: 1-12.

[46] Zakeri A, Khaseb S, Akhavan Rahnama M, Hajaliaskari A, Soufi ZM. Exosomes derived from mesenchymal stem cells: a promising cell-free therapeutic tool for cutaneous wound healing. Biochimie. 2023; 209: 73-84.

[47] Joorabloo A, Liu T. Engineering exosome-based biomimetic nanovehicles for wound healing. J Control Release. 2023; 356: 463-80.

[48] Jadli AS, Ballasy N, Edalat P, Patel VB. Inside (sight) of tiny communicator: exosome biogenesis, secretion, and uptake. Mol Cell Biochem. 2020; 467: 77-94.

[49] Yue B, Yang H, Wang J, Ru W, Wu J, Huang Y, et al. Exosome biogenesis, secretion and function of exosomal miRNAs in skeletal muscle myogenesis. Cell Prolif. 2020; 53: e12857.

[50] Kita S, Shimomura I. Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes. The Journal of Biochemistry. 2021; 169: 173-9.

[51] Fordjour FK, Daaboul GG, Gould SJ. A shared pathway of exosome biogenesis operates at plasma and endosome membranes. BioRxiv. 2019; 545228.

[52] Jia X, Yin Y, Chen Y, Mao L. The role of viral proteins in the regulation of exosomes biogenesis. Front Cell Infect Microbiol. 2021; 11: 671625.

[53] Burkova EE, Sedykh SE, Nevinsky GA.Human placenta exosomes: biogenesis, isolation, composition, and prospects for use in diagnostics. Int J Mol Sci. 2021; 22: 2158.

[54] Mashouri L, Yousefi H, Aref AR, Am A, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019; 18: 1-14.

[55] Sundar V, Saraswathi V. Effect of ethanol on exosome biogenesis: possible mechanisms and therapeutic implications. Biomol Ther. 2023; 13: 222.

[56] Amini H, Rezabakhsh A, Heidarzadeh M, Hassanpour M, Hashemzadeh S, Ghaderi S, et al. An examination of the putative role of melatonin in exosome biogenesis. Frontiers in Cell and Developmental Biology. 2021; 9: 686551.

[57] Xie S, Zhang Q, Jiang L. Current knowledge on exosome biogenesis, cargo-sorting mechanism and therapeutic implications. Membranes. 2022; 12: 498.

[58] Sancho-Albero M, del Mar E-BM, Beltran-Visiedo M, Fernandez-Messina L, Sebastian V, Sanchez-Madrid F, et al. Efficient encapsulation of theranostic nanoparticles in cell-derived exosomes: leveraging the exosomal biogenesis pathway to obtain hollow gold nanoparticle-hybrids. Nanoscale. 2019; 11: 18825-36.

[59] Thakur A, Parra DC, Motallebnejad P, Brocchi M, Chen HJ. Exosomes: small vesicles with big roles in cancer, vaccine development, and therapeutics. Bioactive materials. 2022; 10: 281-94.

[60] Lu M, Huang Y. Bioinspired exosome-like therapeutics and delivery nanoplatforms. Biomaterials. 2020; 242: 119925.

[61] He X, Dong Z, Cao Y, Wang H, Liu S, Liao L, et al. MSC-derived exosome promotes M2 polarization and enhances cutaneous wound healing. Stem Cells Int. 2019; 2019: 1-16.

[62] Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, et al. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015; 13: 308.

[63] Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018; 156: 16-27.

[64] Shen C, Tao C, Zhang A, Li X, Guo Y, Wei H, et al. Exosomal microRNA-93-3p secreted by bone marrow mesenchymal stem cells downregulates apoptotic peptidase activating factor 1 to promote wound healing. Bioengineered. 2022; 13: 27-37.

[65] Ma T, Fu B, Yang X, Xiao Y, Pan M. Adipose mesenchymal stem cell-derived exosomes promote cell proliferation, migration, and inhibit cell apoptosis via Wnt/β-catenin signaling in cutaneous wound healing. J Cell Biochem. 2019; 120: 10847-54.

[66] Kastelowitz N, Yin H. Exosomes and microvesicles: identification and targeting by particle size and lipid chemical probes. Chembiochem. 2014; 15: 923-8.

[67] Skotland T, Ekroos K, Kauhanen D, Simolin H, Seierstad T, Berge V, et al. Molecular lipid species in urinary exosomes as potential prostate cancer biomarkers. Eur J Cancer. 2017; 70: 122-32.

[68] Huang Y, Liu L, Wu J, Li Y. Physiological role of circulating exosomes on hepatic lipid metabolism disorder in ketosis dairy cows. Chinese Journal of Animal Nutrition. 2019; 31: 3004-8.

[69] Lundberg S, Karlsson E, Dahlberg H, Glansk M, Larsson S, Larsson S, et al. Exosomes and lipid nanoparticles-the future of targeted drug delivery. Diva, Sweden, 2020.

[70] Skryabin G, Komelkov A, Savelyeva E, Tchevkina E. Lipid rafts in exosome biogenesis. Biochem Mosc. 2020; 85: 177-91.

[71] Liu Z, Cao K, Liao Z, Chen Y, Lei X, Wei Q, et al. Monophosphoryl lipid a alleviated radiation-induced testicular injury through TLR4-dependent exosomes. J Cell Mol Med. 2020; 24: 3917-30.

[72] Sakai-Kato K, Yoshida K, Takechi-Haraya Y, Izutsu K-I. Physicochemical characterization of liposomes that mimic the lipid composition of exosomes for effective intracellular trafficking. Langmuir. 2020; 36: 12735-44.

[73] Mańka R, Janas P, Sapoń K, Janas T, Janas T. Role of RNA motifs in RNA interaction with membrane lipid rafts: implications for therapeutic applications of exosomal RNAs. Int J Mol Sci. 2021; 22: 9416.

[74] Hullin-Matsuda F, Colosetti P, Rabia M, Luquain-Costaz C, Delton I. Exosomal lipids from membrane organization to biomarkers: focus on an endolysosomal-specific lipid. Biochimie. 2022; 203: 77-92.

[75] Tenchov R, Sasso JM, Wang X, Liaw W-S, Chen C-A, Zhou QA. Exosomes-Nature’s lipid nanoparticles, a rising star in drug delivery and diagnostics. ACS Nano. 2022; 16: 17802-46.

[76] Biadglegne F, Schmidt JR, Engel KM, Lehmann J, Lehmann RT, Reinert A, et al. Mycobacterium tuberculosis affects protein and lipid content of circulating exosomes in infected patients depending on tuberculosis disease state. Biomedicines. 2022; 10: 783.

[77] Staals RH, Pruijn GJ. The human exosome and disease. RNA Exosome. 2010; 132-42.

[78] Brouwer R, Allmang C, Raijmakers R, Van Aarssen Y, Egberts WV, Petfalski E, et al. Three novel components of the human exosome. J Biol Chem. 2001; 276: 6177-84.

[79] Ludwig N, Whiteside TL, Reichert TE. Challenges in exosome isolation and analysis in health and disease. Int J Mol Sci. 2019; 20: 4684.

[80] Wan J, Yourshaw M, Mamsa H, Rudnik-Schöneborn S, Menezes MP, Hong JE, et al. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet. 2012; 44: 704-8.

[81] Allmang C, Mitchell P, Petfalski E, Tollervey D. Degradation of ribosomal RNA precursors by the exosome. Nucleic Acids Res. 2000; 28: 1684-91.

[82] Wan Z, Gao X, Dong Y, Zhao Y, Chen X, Yang G, et al. Exosome-mediated cell-cell communication in tumor progression. Am J Cancer Res. 2018; 8: 1661-73.

[83] Hu Y, Tao R, Chen L, Xiong Y, Xue H, Hu L, et al. Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis. Journal of nanobiotechnology. 2021; 19: 1-17.

[84] Larabi A, Barnich N, Nguyen HTT. Emerging role of exosomes in diagnosis and treatment of infectious and inflammatory bowel diseases. Cells. 2020; 9: 1111.

[85] Abramowicz A, Marczak L, Wojakowska A, Zapotoczny S, Whiteside TL, Widlak P, et al. Harmonization of exosome isolation from culture supernatants for optimized proteomics analysis. PLoS One. 2018; 13: e0205496.

[86] Sibley CR, Seow Y, Curtis H, Weinberg MS, Wood MJ. Silencing of Parkinson’s disease-associated genes with artificial mirtron mimics of miR-1224. Nucleic Acids Res. 2012; 40: 9863-75.

[87] Andalib E, Kashfi M, Mahmoudvand G, Rezaei E, Mahjoor M, Torki A, et al. Application of hypoxia-mesenchymal stem cells in treatment of anaerobic bacterial wound infection: wound healing and infection recovery. 2023; 14: 1251956.

[88] Chiriacò MS, Bianco M, Nigro A, Primiceri E, Ferrara F, Romano A, et al. Lab-on-chip for exosomes and microvesicles detection and characterization. Sensors. 2018; 18: 3175.

[89] Zhang M, Jin K, Gao L, Zhang Z, Li F, Zhou F, et al. Methods and technologies for exosome isolation and characterization. Small Methods. 2018; 2: 1800021.

[90] Li J, Chen X, Yi J, Liu Y, Li D, Wang J, et al. Identification and characterization of 293T cell-derived exosomes by profiling the protein, mRNA and microRNA components. PLoS One. 2016; 11: e0163043.

[91] Anand S, Samuel M, Kumar S, Mathivanan S. Ticket to a bubble ride: cargo sorting into exosomes and extracellular vesicles. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics. 2019; 1867: 140203.

[92] Hood JL.Post isolation modification of exosomes for nanomedicine applications. Nanomedicine. 2016; 11: 1745-56.

[93] Zipkin M. Exosome redux. Nat Biotechnol. 2019; 37: 1395-400.

[94] Yang G, Waheed S, Wang C, Shekh M, Li Z, Wu J. Exosomes and their bioengineering strategies in the cutaneous wound healing and related complications: current knowledge and future perspectives. Int J Biol Sci. 2023; 19: 1430-54.

[95] Peterson MF, Otoc N, Sethi JK, Gupta A, Antes TJ. Integrated systems for exosome investigation. Methods. 2015; 87: 31-45.

[96] Beit-Yannai E, Tabak S, Stamer WD. Physical exosome: exosome interactions. J Cell Mol Med. 2018; 22: 2001-6.

[97] Balbi C, Vassalli G. Exosomes: beyond stem cells for cardiac protection and repair. Stem Cells. 2020; 38: 1387-99.

[98] Meola N, Domanski M, Karadoulama E, Chen Y, Gentil C, Pultz D, et al. Identification of a nuclear exosome decay pathway for processed transcripts. Mol Cell. 2016; 64: 520-33.

[99] Waligorska A, Dobrucki JW, Mytar B, Szczepanik A, Siedlar M, Drabik G, et al. Interactions of tumour-derived micro (nano) vesicles with human gastric cancer cells. J Transl Med. 2015; 13: 376. https://doi.org/10.1186/s12967-015-0737-0.

[100] Sluijter JP, Verhage V, Deddens JC, van den Akker F, Doevendans PA. Microvesicles and exosomes for intracardiac communication. Cardiovasc Res. 2014; 102: 302-11.

[101] Lázaro-Ibáñez E, Sanz-Garcia A, Visakorpi T, Escobedo-Lucea C, Siljander P, Ayuso-Sacido Á, et al. Different gDNA content in the subpopulations of prostate cancer extracellular vesicles: apoptotic bodies, microvesicles, and exosomes. Prostate. 2014; 74: 1379-90.

[102] Dragovic R, Collett G, Hole P, Ferguson D, Redman C, Sargent I, et al. Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence nanoparticle tracking analysis. Methods. 2015; 87: 64-74.

[103] Lawson C, Vicencio JM, Yellon DM, Davidson SM. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol. 2016; 228: R57-71.

[104] Sun Y, Huo C, Qiao Z, Shang Z, Uzzaman A, Liu S, et al. Comparative proteomic analysis of exosomes and microvesicles in human saliva for lung cancer. J Proteome Res. 2018; 17: 1101-7.

[105] Dini L, Tacconi S, Carata E, Tata A, Vergallo C, Panzarini E. Microvesicles and exosomes in metabolic diseases and inflammation. Cytokine Growth Factor Rev. 2020; 51: 27-39.

[106] Varela-Eirin M, Varela-Vazquez A, Mateos MR-C, Vila-Sanjurjo A, Fonseca E, Mascarenas JL, et al. Recruitment of RNA molecules by connexin RNA-binding motifs: implication in RNA and DNA transport through microvesicles and exosomes. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2017; 1864: 728-36.

[107] Yang Y, Bucan V, Baehre H, Von Der Ohe J, Otte A, Hass R. Acquisition of new tumor cell properties by MSC-derived exosomes. Int J Oncol. 2015; 47: 244-52.

[108] Lou R, Chen J, Zhou F, Wang C, Leung C-H, Lin L. Exosome-cargoed microRNAs: potential therapeutic molecules for diabetic wound healing. Drug Discov Today. 2022; 27: 103323.

[109] Han S, Underwood P, Hughes SJ. From tumor microenvironment communicants to biomarker discovery: selectively packaged extracellular vesicular cargoes in pancreatic cancer. Cytokine Growth Factor Rev. 2020; 51: 61-8.

[110] Lim CZ, Natalia A, Sundah NR, Shao H. Biomarker organization in circulating extracellular vesicles: new applications in detecting neurodegenerative diseases. Advanced Biosystems. 2020; 4: e1900309.

[111] Elewaily MI, Elsergany AR. Emerging role of exosomes and exosomal microRNA in cancer: pathophysiology and clinical potential. J Cancer Res Clin Oncol. 2021; 147: 637-48.

[112] Whiteside TL.Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem. 2016; 74: 103-41.

[113] Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M (eds). Sorting it out: regulation of exosome loading. Seminars in cancer biology. USA: Academic Press Ltd, Elsevier Science Ltd, 2014, editors.

[114] Greening DW, Simpson RJ. Understanding extracellular vesicle diversity-current status. Expert review of proteomics. 2018; 15: 887-910.

[115] Hariharan H, Kesavan Y, Raja NS. Impact of native and external factors on exosome release: understanding reactive exosome secretion and its biogenesis. Mol Biol Rep. 2021; 48: 7559-73.

[116] Rangel-Ramírez VV, González-Sánchez HM, Lucio-García C. Exosomes: from biology to immunotherapy in infectious diseases. Infectious Diseases. 2023; 55: 79-107.

[117] Yue S, Mu W, Erb U, Zöller M. The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. Oncotarget. 2015; 6: 2366-84.

[118] Lai RC, RWY Y, Lim SK (eds). Mesenchymal stem cell exosomes. Seminars in cell & developmental biology. Elsevier, 2015, editors.

[119] Xiong Y, Feng Q, Lu L, Zha K, Yu T, Lin Z, et al. Immunomodulatory hydrogels: advanced regenerative tools for diabetic foot ulcer. Adv Funct Mater. 2023; 33: 2213066.

[120] Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018; 75: 193-208.

[121] Xiong Y, Lin Z, Bu P, Yu T, Endo Y, Zhou W, et al. A whole-course-repair system based on neurogenesis-angiogenesis crosstalk and macrophage reprogramming promotes diabetic wound healing. Adv Mater. 2023; 35: e2212300.

[122] Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release. 2015; 219: 278-94.

[123] Zarovni N, Corrado A, Guazzi P, Zocco D, Lari E, Radano G, et al. Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches. Methods. 2015; 87: 46-58.

[124] Okonkwo UA, Chen L, Ma D, Haywood VA, Barakat M, Urao N, et al. Compromised angiogenesis and vascular integrity in impaired diabetic wound healing. PLoS One. 2020; 15: e0231962.

[125] Singh K, Sinha M, Pal D, Tabasum S, Gnyawali SC, Khona D, et al. Cutaneous epithelial to mesenchymal transition activator ZEB1 regulates wound angiogenesis and closure in a glycemic status-dependent manner. Diabetes. 2019; 68: 2175-90.

[126] Yang JM, Ryu J, Kim I, Chang H, Kim I-K. Dll4 blockade promotes angiogenesis in nonhealing wounds of Sox7-deficient mice. Advances in Wound Care. 2020; 9: 591-601.

[127] Long G, Liu D, He X, Shen Y, Zhao Y, Hou X, et al. A dual functional collagen scaffold coordinates angiogenesis and inflammation for diabetic wound healing. Biomaterials Science. 2020; 8: 6337-49.

[128] Wang M, Wang C, Chen M, Xi Y, Cheng W, Mao C, et al. Efficient angiogenesis-based diabetic wound healing/skin reconstruction through bioactive antibacterial adhesive ultraviolet shielding nanodressing with exosome release. ACS Nano. 2019; 13: 10279-93.

[129] Tu Z, Chen M, Wang M, Shao Z, Jiang X, Wang K, et al. Engineering bioactive M2 macrophage-polarized anti-inflammatory, antioxidant, and antibacterial scaffolds for rapid angiogenesis and diabetic wound repair. Adv Funct Mater. 2021; 31: 2100924.

[130] Wu S-C, Kuo P-J, Rau C-S, Huang L-H, Lin C-W, Wu Y-C, et al. Increased angiogenesis by exosomes secreted by adipose-derived stem cells upon lipopolysaccharide stimulation. Int J Mol Sci. 2021; 22: 8877.

[131] Martin P, Gurevich DB (eds). Macrophage regulation of angiogenesis in health and disease. Seminars in Cell & Developmental Biology. Elsevier, 2021.

[132] Noishiki C, Yuge S, Ando K, Wakayama Y, Mochizuki N, Ogawa R, et al. Live imaging of angiogenesis during cutaneous wound healing in adult zebrafish. Angiogenesis. 2019; 22: 341-54.

[133] Rebling J, Ben-Yehuda Greenwald M, Wietecha M, Werner S, Razansky D. Long-term imaging of wound angiogenesis with large scale optoacoustic microscopy. Advanced Science. 2021; 8: 2004226.

[134] Zahm JM, Kaplan H, Hérard AL, Doriot F, Pierrot D, Somelette P, et al. Cell migration and proliferation during the in vitro wound repair of the respiratory epithelium. Cell Motil Cytoskeleton. 1997; 37: 33-43.

[135] Alizadeh S, Seyedalipour B, Shafieyan S, Kheime A, Mohammadi P, Aghdami N. Copper nanoparticles promote rapid wound healing in acute full thickness defect via acceleration of skin cell migration, proliferation, and neovascularization. Biochem Biophys Res Commun. 2019; 517: 684-90.

[136] Akrami-Hasan-Kohal M, Tayebi L, Ghorbani M. Curcumin-loaded naturally-based nanofibers as active wound dressing mats: morphology, drug release, cell proliferation, and cell adhesion studies. New J Chem. 2020; 44: 10343-51.

[137] Paddle-Ledinek JE, Nasa Z, Cleland HJ. Effect of different wound dressings on cell viability and proliferation. Plast Reconstr Surg. 2006; 117: 110S-8.

[138] Kruse CR, Singh M, Targosinski S, Sinha I, Sørensen JA, Eriksson E, et al. The effect of pH on cell viability, cell migration, cell proliferation, wound closure, and wound reepithelialization: In vitro and in vivo study. Wound Repair Regen. 2017; 25: 260-9.

[139] Zeng QL, Liu DW. Mesenchymal stem cell-derived exosomes: An emerging therapeutic strategy for normal and chronic wound healing. World journal of clinical cases. 2021; 9: 6218-33.

[140] Kaleci B, Koyuturk M. Efficacy of resveratrol in the wound healing process by reducing oxidative stress and promoting fibroblast cell proliferation and migration. Dermatol Ther. 2020; 33: e14357.

[141] Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell proliferation by chronic wound fluid. Wound Repair Regen. 1993; 1: 181-6.

[142] Soliman AM, Das S, Abd Ghafar N, Teoh SL. Role of microRNA in proliferation phase of wound healing. Front Genet. 2018; 9: 38.

[143] Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci. 2016; 73: 3861-85.

[144] Saxena V, Hwang C-W, Huang S, Eichbaum Q, Ingber D, Orgill DP. Vacuum-assisted closure: microdeformations of wounds and cell proliferation. Plast Reconstr Surg. 2004; 114: 1086-96.

[145] Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007; 25: 9-18.

[146] Ellis S, Lin EJ, Tartar D. Immunology of wound healing. Curr Derm Rep. 2018; 7: 350-8.

[147] Ding J-Y, Chen M-J, Wu L-F, Shu G-F, Fang S-J, Li Z-Y, et al. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Military Medical Research. 2023; 10: 36.

[148] Zhao X, Zhang W, Fan J, Chen X, Wang X. Application of mesenchymal stem cell exosomes in the treatment of skin wounds. Smart Materials in Medicine. 2023; 4: 578-89.

[149] Pelizzo G, Avanzini M. A, Icaro Cornaglia A, De Silvestri A, Mantelli M, Travaglino P, et al. Extracellular vesicles derived from mesenchymal cells: perspective treatment for cutaneous wound healing in pediatrics. Regen Med. 2018; 13: 385-394. https://doi.org/10.2217/rme-2018-0001.

[150] Djalilian AR, McGaughey D, Patel S, Seo EY, Yang C, Cheng J, et al. Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response. J Clin Invest. 2006; 116: 1243-53.

[151] Zhang B, Gong J, He L, Khan A, Xiong T, Shen H, et al. Exosomes based advancements for application in medical aesthetics. Frontiers in bioengineering and biotechnology. 2022; 10: 1083640.

[152] Fekrazad R, Sarrafzadeh A, Kalhori KA, Khan I, Arany PR, Giubellino A. Improved wound remodeling correlates with modulated TGF-beta expression in skin diabetic wounds following combined red and infrared photobiomodulation treatments. Photochem Photobiol. 2018; 94: 775-9.

[153] Sousa P, Lopes B, Sousa AC, Moreira A, Coelho A, Alvites R, et al. Advancements and insights in exosome-based therapies for wound healing: a comprehensive systematic review (2018-June 2023). Biomedicines. 2023; 11: 2099.

[154] Ye H, Wang F, Xu G, Shu F, Fan K, Wang D. Advancements in engineered exosomes for wound repair: current research and future perspectives. Frontiers in bioengineering and biotechnology. 2023; 11: 11.

[155] Xiong Y, Mi BB, Lin Z, Hu YQ, Yu L, Zha KK, et al. The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity. Mil Med Res. 2022; 9: 65.

[156] Bian D, Wu Y, Song G, Azizi R, Zamani A. The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review. Stem Cell Res Ther. 2022; 13: 24.

[157] Mahmoudvand G, Karimi Rouzbahani A, Razavi ZS, Mahjoor M, Afkhami H. Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: new insight. Front Bioeng Biotechnol. 2023; 11: 1158484.

[158] Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax. 2012; 67: 533-9.

[159] Maqbool M, Vidyadaran S, George E, Ramasamy R. Human mesenchymal stem cells protect neutrophils from serum-deprived cell death. Cell Biol Int. 2011; 35: 1247-51.

[160] Raghav A, Tripathi P, Mishra BK, Jeong GB, Banday S, Gautam KA, et al. Mesenchymal stromal cell-derived tailored exosomes treat bacteria-associated diabetes foot ulcers: a customized approach from bench to bed. Front Microbiol. 2021; 12: 712588.

[161] Marx C, Gardner S, Harman RM, Wagner B, van de Walle GR. Mesenchymal stromal cell-secreted CCL2 promotes antibacterial defense mechanisms through increased antimicrobial peptide expression in keratinocytes. Stem Cells Transl Med. 2021; 10: 1666-79.

[162] Qian Z, Bai Y, Zhou J, Li L, Na J, Fan Y, et al. A moisturizing chitosan-silk fibroin dressing with silver nanoparticles-adsorbed exosomes for repairing infected wounds. J Mater Chem B. 2020; 8: 7197-212.

[163] Sun B, Wu F, Wang X, Song Q, Ye Z, Mohammadniaei M, et al. An optimally designed engineering exosome-reductive COF integrated Nanoagent for synergistically enhanced diabetic fester wound healing. Small. 2022; 18: e2200895.