Skip to main content

Advertisement

SpringerLink
Log in

The mechanisms of exosomes in diabetic foot ulcers healing: a detailed review

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

As time goes by, the morbidity of diabetes mellitus continues to rise, and the economic burden of diabetic foot ulcers as a common and serious complication of diabetes is increasing. However, currently there is no unified clinical treatment strategy for this complication, and the therapeutic efficacy is unsatisfactory. Recent studies have revealed that biological effects of exosomes involved in multiple stages of the process of wound closure are similar to source cells. Compared with source cells, exosomes possess lowly immunogenicity, highly stability and easily stored, etc. Accumulating evidence confirmed that exosomes promote diabetic wound healing through various pathways such as promoting angiogenesis, collagen fiber deposition, and inhibiting inflammation. The superior therapeutic efficacy of exosomes in accelerating diabetic cutaneous wound healing has attracted an increasing attention. Notably, the molecular mechanisms of exosomes vary among different sources in the chronic wound closure of diabetes. This review focuses on the specific roles and mechanisms of different cell- or tissue-derived exosomes relevant to wound healing. Additionally, the paper provides an overview of the current pre-clinical and clinical applications of exosomes, illustrates their special advantages in wound repair. Furthermore, we discuss the potential obstacles and various solutions for future research on exosomes in the management of diabetic foot ulcer. The aim is to offer novel insights and approaches for the treatment of diabetic foot ulcer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Armstrong DG, Boulton AJM, Bus SA (2017) Diabetic foot ulcers and their recurrence. N Engl J Med 376(24):2367–2375. https://doi.org/10.1056/NEJMra1615439

    Article  PubMed  Google Scholar 

  2. Walsh JW, Hoffstad OJ, Sullivan MO, Margolis DJ (2016) Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med 33(11):1493–1498. https://doi.org/10.1111/dme.13054

    Article  CAS  PubMed  Google Scholar 

  3. Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, Schaper N (2007) High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 50(1):18–25. https://doi.org/10.1007/s00125-006-0491-1

  4. Diegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 9:283–289. https://doi.org/10.2741/1184

    Article  CAS  PubMed  Google Scholar 

  5. Chang M, Nguyen TT (2021) Strategy for treatment of infected diabetic foot ulcers. Acc Chem Res 54(5):1080–1093. https://doi.org/10.1021/acs.accounts.0c00864

    Article  CAS  PubMed  Google Scholar 

  6. Chudzik W, Kaczorowska B, Przybyla M, Chudzik B, Galka M (2007) Diabetic neuropathy (Neuropatia cukrzycowa). Pol Merkur Lekarski 22(127):66–69. https://www.ncbi.nlm.nih.gov/pubmed/17477095

  7. Kanter JE, Averill MM, Leboeuf RC, Bornfeldt KE (2008) Diabetes-accelerated atherosclerosis and inflammation. Circ Res 103(8):e116-117. https://doi.org/10.1161/CIRCRESAHA.108.182642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Salazar JJ, Ennis WJ, Koh TJ (2016) Diabetes medications: impact on inflammation and wound healing. J Diabetes Complications 30(4):746–752. https://doi.org/10.1016/j.jdiacomp.2015.12.017

    Article  PubMed  Google Scholar 

  9. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC (2019) Wound healing: a cellular perspective. Physiol Rev 99(1):665–706. https://doi.org/10.1152/physrev.00067.2017

    Article  CAS  PubMed  Google Scholar 

  10. Guan Y, Niu H, Liu Z, Dang Y, Shen J, Zayed M, Guan J (2021) Sustained oxygenation accelerates diabetic wound healing by promoting epithelialization and angiogenesis and decreasing inflammation. Sci Adv 7(35). https://doi.org/10.1126/sciadv.abj0153

  11. Vulliet PR, Greeley M, Halloran SM, MacDonald KA, Kittleson MD (2004) Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet 363(9411):783–784. https://doi.org/10.1016/S0140-6736(04)15695-X

    Article  PubMed  Google Scholar 

  12. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Lyden D (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527(7578):329–335. https://doi.org/10.1038/nature15756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY (2018) New insights into TGF-beta/Smad signaling in tissue fibrosis. Chem Biol Interact 292:76–83. https://doi.org/10.1016/j.cbi.2018.07.008

    Article  CAS  PubMed  Google Scholar 

  14. Kalluri R, LeBleu VS (2020) The biology, function, and biomedical applications of exosomes. Science 367(6478). https://doi.org/10.1126/science.aau6977

  15. Li P, Kaslan M, Lee SH, Yao J, Gao Z (2017) Progress in exosome isolation techniques Theranostics 7(3):789–804. https://doi.org/10.7150/thno.18133

    Article  CAS  PubMed  Google Scholar 

  16. Lin J, Wang Z, Huang J, Tang S, Saiding Q, Zhu Q, Cui W (2021) Microenvironment-protected exosome-hydrogel for facilitating endometrial regeneration, fertility restoration, and live birth of offspring. Small 17(11):e2007235. https://doi.org/10.1002/smll.202007235

  17. Yan Y, Jiang W, Tan Y, Zou S, Zhang H, Mao F, Xu W (2017) hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther 25(2):465–479. https://doi.org/10.1016/j.ymthe.2016.11.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zheng D, Huo M, Li B, Wang W, Piao H, Wang Y, Liu K (2020) The role of exosomes and exosomal microRNA in cardiovascular disease. Front Cell Dev Biol 8:616161. https://doi.org/10.3389/fcell.2020.616161

  19. Li D, Wu N (2022) Mechanism and application of exosomes in the wound healing process in diabetes mellitus. Diabetes Res Clin Pract 187:109882. https://doi.org/10.1016/j.diabres.2022.109882

  20. He C, Zheng S, Luo Y, Wang B (2018) Exosome theranostics: biology and translational medicine. Theranostics 8(1):237–255. https://doi.org/10.7150/thno.21945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhao R, Zhao T, He Z, Cai R, Pang W (2021) Composition, isolation, identification and function of adipose tissue-derived exosomes. Adipocyte 10(1):587–604. https://doi.org/10.1080/21623945.2021.1983242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang D, Zhang W, Zhang H, Zhang F, Chen L, Ma L, Wang T (2020) Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics. Theranostics 10(8):3684–3707. https://doi.org/10.7150/thno.41580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Momen-Heravi F (2017) Isolation of extracellular vesicles by ultracentrifugation. Methods Mol Biol 1660:25–32. https://doi.org/10.1007/978-1-4939-7253-1_3

    Article  CAS  PubMed  Google Scholar 

  24. Shu S, Yang Y, Allen CL, Hurley E, Tung KH, Minderman H, Ernstoff MS (2020) Purity and yield of melanoma exosomes are dependent on isolation method. J Extracell Vesicles 9(1):1692401. https://doi.org/10.1080/20013078.2019.1692401

    Article  CAS  PubMed  Google Scholar 

  25. Jiawei S, Zhi C, Kewei T, Xiaoping L (2022) Magnetic bead-based adsorption strategy for exosome isolation. Front Bioeng Biotechnol 10:942077. https://doi.org/10.3389/fbioe.2022.942077

  26. Keshtkar S, Azarpira N, Ghahremani MH (2018) Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther 9(1):63. https://doi.org/10.1186/s13287-018-0791-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu P, Zhang B, Shi H, Qian H, Xu W (2018) MSC-exosome: a novel cell-free therapy for cutaneous regeneration. Cytotherapy 20(3):291–301. https://doi.org/10.1016/j.jcyt.2017.11.002

    Article  PubMed  Google Scholar 

  28. Li J, Komatsu H, Poku EK, Olafsen T, Huang KX, Huang LA, Kandeel FR (2022) Biodistribution of intra-arterial and intravenous delivery of human umbilical cord mesenchymal stem cell-derived extracellular vesicles in a rat model to guide delivery strategies for diabetes therapies. Pharmaceuticals (Basel) 15(5). https://doi.org/10.3390/ph15050595

  29. Jiang S, Xu L (2020) Exosomes from gingival mesenchymal stem cells enhance migration and osteogenic differentiation of pre-osteoblasts. Pharmazie 75(11):576–580. https://doi.org/10.1691/ph.2020.0652

    Article  CAS  PubMed  Google Scholar 

  30. Hu Y, Tao R, Chen L, Xiong Y, Xue H, Hu L, Liu G (2021) Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis. J Nanobiotechnology 19(1):150. https://doi.org/10.1186/s12951-021-00894-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee HD, Kim YH, Kim DS (2014) Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking. Eur J Immunol 44(4):1156–1169. https://doi.org/10.1002/eji.201343660

    Article  CAS  PubMed  Google Scholar 

  32. Mi B, Chen L, Xiong Y, Yan C, Xue H, Panayi AC, Liu G (2020) Saliva exosomes-derived UBE2O mRNA promotes angiogenesis in cutaneous wounds by targeting SMAD6. J Nanobiotechnology 18(1):68. https://doi.org/10.1186/s12951-020-00624-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Park GH, Kwon HH, Seok J, Yang SH, Lee J, Park BC, Park KY (2023) Efficacy of combined treatment with human adipose tissue stem cell-derived exosome-containing solution and microneedling for facial skin aging: A 12-week prospective, randomized, split-face study. J Cosmet Dermatol. https://doi.org/10.1111/jocd.15872

    Article  PubMed  Google Scholar 

  34. Shi Q, Qian Z, Liu D, Sun J, Wang X, Liu H, Guo X (2017) GMSC-derived exosomes combined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model. Front Physiol 8:904. https://doi.org/10.3389/fphys.2017.00904

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tao SC, Guo SC, Li M, Ke QF, Guo YP, Zhang CQ (2017) Chitosan wound dressings incorporating exosomes derived from microRNA-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model. Stem Cells Transl Med 6(3):736–747. https://doi.org/10.5966/sctm.2016-0275

    Article  CAS  PubMed  Google Scholar 

  36. Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Han W (2015) LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med 13:308. https://doi.org/10.1186/s12967-015-0642-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang J, Wu H, Peng Y, Zhao Y, Qin Y, Zhang Y, Xiao Z (2021) Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K/Akt pathways. J Nanobiotechnology 19(1):202. https://doi.org/10.1186/s12951-021-00942-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang R, Ji Q, Meng C, Liu H, Fan C, Lipkind S, Xu Q (2020) Role of gingival mesenchymal stem cell exosomes in macrophage polarization under inflammatory conditions. Int Immunopharmacol 81:106030. https://doi.org/10.1016/j.intimp.2019.106030

  39. Wu D, Kang L, Tian J, Wu Y, Liu J, Li Z, Qiu G (2020) Exosomes derived from bone mesenchymal stem cells with the stimulation of Fe3O4 nanoparticles and static magnetic field enhance wound healing through upregulated miR-21-5p. Int J Nanomedicine 15:7979–7993. https://doi.org/10.2147/IJN.S275650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang J, Chen Z, Pan D, Li H, Shen J (2020) Umbilical cord-derived mesenchymal stem cell-derived exosomes combined pluronic F127 hydrogel promote chronic diabetic wound healing and complete skin regeneration. Int J Nanomedicine 15:5911–5926. https://doi.org/10.2147/IJN.S249129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, Xu W (2015) HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 33(7):2158–2168. https://doi.org/10.1002/stem.1771

    Article  CAS  PubMed  Google Scholar 

  42. Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q, Wang Y (2015) Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med 13:49. https://doi.org/10.1186/s12967-015-0417-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang X, Jiang Y, Huang Q, Wu Z, Pu H, Xu Z, Peng Z (2021) Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia. Stem Cell Res Ther 12(1):403. https://doi.org/10.1186/s13287-021-02475-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang Y, Yan J, Liu Y, Chen Z, Li X, Tang L, Zhang G (2021) Human amniotic fluid stem cell-derived exosomes as a novel cell-free therapy for cutaneous regeneration. Front Cell Dev Biol 9:685873. https://doi.org/10.3389/fcell.2021.685873

  45. Zhao B, Li X, Shi X, Shi X, Zhang W, Wu G, Hu D (2018) Exosomal microRNAs derived from human amniotic epithelial cells accelerate wound healing by promoting the proliferation and migration of fibroblasts. Stem Cells Int 2018:5420463. https://doi.org/10.1155/2018/5420463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li X, Xie X, Lian W, Shi R, Han S, Zhang H, Li M (2018) Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med 50(4):1–14. https://doi.org/10.1038/s12276-018-0058-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ma T, Fu B, Yang X, Xiao Y, Pan M (2019) Adipose mesenchymal stem cell-derived exosomes promote cell proliferation, migration, and inhibit cell apoptosis via Wnt/beta-catenin signaling in cutaneous wound healing. J Cell Biochem 120(6):10847–10854. https://doi.org/10.1002/jcb.28376

    Article  CAS  PubMed  Google Scholar 

  48. Shiekh PA, Singh A, Kumar A (2020) Exosome laden oxygen releasing antioxidant and antibacterial cryogel wound dressing OxOBand alleviate diabetic and infectious wound healing. Biomaterials 249:120020. https://doi.org/10.1016/j.biomaterials.2020.120020

  49. Wang C, Wang M, Xu T, Zhang X, Lin C, Gao W, Mao C (2019) Engineering bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration. Theranostics 9(1):65–76. https://doi.org/10.7150/thno.29766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhou Y, Zhao B, Zhang XL, Lu YJ, Lu ST, Cheng J, Zhang J (2021) Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration. Stem Cell Res Ther 12(1):257. https://doi.org/10.1186/s13287-021-02287-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang L, Ouyang P, He G, Wang X, Song D, Yang Y, He X (2021) Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway. J Cell Mol Med 25(4):2148–2162. https://doi.org/10.1111/jcmm.16192

    Article  CAS  PubMed  Google Scholar 

  52. Shen K, Wang XJ, Liu KT, Li SH, Li J, Zhang JX, Wang HT, Hu DH (2022) Effects of exosomes from human adipose-derived mesenchymal stem cells on inflammatory response of mouse RAW264. 7 cells and wound healing of full-thickness skin defects in mice. Zhonghua Shao Shang Za Zhi 38(3):215–226

  53. Liu D, Cao Y, Jiang P, Wang Y, Lu Y, Ji Z, Liu W (2023) Tough, Transparent, and Slippery PVA Hydrogel Led by Syneresis. Small 19(14):e2206819. https://doi.org/10.1002/smll.202206819

  54. Xin Zhou WY, Zhang X (2021) Preparation of mesenchymal stem cell exosome-thermosensitive hydrogel and its application in epidermal wound repair. Chin J Pharm 52(09):1199–1207 (in Chinese)

  55. Kwon HH, Yang SH, Lee J, Park BC, Park KY, Jung JY, Park GH (2020) Combination treatment with human adipose tissue stem cell-derived exosomes and fractional CO2 laser for acne scars: a 12-week prospective, double-blind, randomized, split-face study. Acta Derm Venereol 100(18):adv00310. https://doi.org/10.2340/00015555-3666

  56. Tutuianu R, Rosca AM, Iacomi DM, Simionescu M, Titorencu I (2021) Human mesenchymal stromal cell-derived exosomes promote in vitro wound healing by modulating the biological properties of skin keratinocytes and fibroblasts and stimulating angiogenesis. Int J Mol Sci 22(12). https://doi.org/10.3390/ijms22126239

  57. Yu M, Liu W, Li J, Lu J, Lu H, Jia W, Liu F (2020) Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway. Stem Cell Res Ther 11(1):350. https://doi.org/10.1186/s13287-020-01824-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ding J, Wang X, Chen B, Zhang J, Xu J (2019) Exosomes derived from human bone marrow mesenchymal stem cells stimulated by deferoxamine accelerate cutaneous wound healing by promoting angiogenesis. Biomed Res Int 2019:9742765. https://doi.org/10.1155/2019/9742765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu J, Yan Z, Yang F, Huang Y, Yu Y, Zhou L, Yan Y (2021) Exosomes derived from human umbilical cord mesenchymal stem cells accelerate cutaneous wound healing by enhancing angiogenesis through delivering angiopoietin-2. Stem Cell Rev Rep 17(2):305–317. https://doi.org/10.1007/s12015-020-09992-7

    Article  CAS  PubMed  Google Scholar 

  60. Yan C, Xv Y, Lin Z, Endo Y, Xue H, Hu Y, Liu G (2022) Human umbilical cord mesenchymal stem cell-derived exosomes accelerate diabetic wound healing via ameliorating oxidative stress and promoting angiogenesis. Front Bioeng Biotechnol 10:829868. https://doi.org/10.3389/fbioe.2022.829868

  61. Fang S, Xu C, Zhang Y, Xue C, Yang C, Bi H, Xing X (2016) Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-beta/SMAD2 pathway during wound healing. Stem Cells Transl Med 5(10):1425–1439. https://doi.org/10.5966/sctm.2015-0367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang Y, Zhang P, Gao X, Chang L, Chen Z, Mei X (2021) Preparation of exosomes encapsulated nanohydrogel for accelerating wound healing of diabetic rats by promoting angiogenesis. Mater Sci Eng C Mater Biol Appl 120:111671. https://doi.org/10.1016/j.msec.2020.111671

  63. Ye C, Zhang Y, Su Z, Wu S, Li Y, Yi J, Zheng Y (2022) hMSC exosomes as a novel treatment for female sensitive skin: an in vivo study. Front Bioeng Biotechnol 10:1053679. https://doi.org/10.3389/fbioe.2022.1053679

    Article  PubMed  PubMed Central  Google Scholar 

  64. Mathew SA, Naik C, Cahill PA, Bhonde RR (2020) Placental mesenchymal stromal cells as an alternative tool for therapeutic angiogenesis. Cell Mol Life Sci 77(2):253–265. https://doi.org/10.1007/s00018-019-03268-1

    Article  CAS  PubMed  Google Scholar 

  65. Komaki M, Numata Y, Morioka C, Honda I, Tooi M, Yokoyama N, Morita I (2017) Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis. Stem Cell Res Ther 8(1):219. https://doi.org/10.1186/s13287-017-0660-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Salomon C, Ryan J, Sobrevia L, Kobayashi M, Ashman K, Mitchell M, Rice GE (2013) Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis. PLoS One 8(7):e68451. https://doi.org/10.1371/journal.pone.0068451

  67. Du W, Zhang K, Zhang S, Wang R, Nie Y, Tao H, Li Z (2017) Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer. Biomaterials 133:70–81. https://doi.org/10.1016/j.biomaterials.2017.04.030

    Article  CAS  PubMed  Google Scholar 

  68. Alcayaga-Miranda F, Cuenca J, Luz-Crawford P, Aguila-Diaz C, Fernandez A, Figueroa FE, Khoury M (2015) Characterization of menstrual stem cells: angiogenic effect, migration and hematopoietic stem cell support in comparison with bone marrow mesenchymal stem cells. Stem Cell Res Ther 6:32. https://doi.org/10.1186/s13287-015-0013-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dalirfardouei R, Jamialahmadi K, Jafarian AH, Mahdipour E (2019) Promising effects of exosomes isolated from menstrual blood-derived mesenchymal stem cell on wound-healing process in diabetic mouse model. J Tissue Eng Regen Med 13(4):555–568. https://doi.org/10.1002/term.2799

    Article  CAS  PubMed  Google Scholar 

  70. Fawzy El-Sayed KM, Dorfer CE (2016) Gingival mesenchymal stem/progenitor cells: a unique tissue engineering gem. Stem Cells Int 2016:7154327. https://doi.org/10.1155/2016/7154327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Burgess DJ (2014) Signalling: vesicle vehicles of genetic information. Nat Rev Genet 15(8):514. https://doi.org/10.1038/nrg3780

    Article  CAS  PubMed  Google Scholar 

  72. Vendramin FS, Franco D, Nogueira CM, Pereira MS, Franco TR (2006) Platelet-rich plasma and growth factors: processing technique and application in plastic surgery. Revista do Colégio Brasileiro de Cirurgiões 33(1)

  73. Guo SC, Tao SC, Yin WJ, Qi X, Yuan T, Zhang CQ (2017) Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics 7(1):81–96. https://doi.org/10.7150/thno.16803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu N, Wang L, Guan J, Tang C, He N, Zhang W, Fu S (2018) Wound healing effects of a Curcuma zedoaria polysaccharide with platelet-rich plasma exosomes assembled on chitosan/silk hydrogel sponge in a diabetic rat model. Int J Biol Macromol 117:102–107. https://doi.org/10.1016/j.ijbiomac.2018.05.066

    Article  CAS  PubMed  Google Scholar 

  75. Li X, Jiang C, Zhao J (2016) Human endothelial progenitor cells-derived exosomes accelerate cutaneous wound healing in diabetic rats by promoting endothelial function. J Diabetes Complications 30(6):986–992. https://doi.org/10.1016/j.jdiacomp.2016.05.009

    Article  PubMed  Google Scholar 

  76. Yi M, Wu Y, Long J, Liu F, Liu Z, Zhang YH, Li J (2019) Exosomes secreted from osteocalcin-overexpressing endothelial progenitor cells promote endothelial cell angiogenesis. Am J Physiol Cell Physiol 317(5):C932–C941. https://doi.org/10.1152/ajpcell.00534.2018

    Article  CAS  PubMed  Google Scholar 

  77. Zhang J, Chen C, Hu B, Niu X, Liu X, Zhang G, Wang Y (2016) Exosomes derived from human endothelial progenitor cells accelerate cutaneous wound healing by promoting angiogenesis through Erk1/2 signaling. Int J Biol Sci 12(12):1472–1487. https://doi.org/10.7150/ijbs.15514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yu Q, Liu L, Zhang X, Chang H, Ma S, Xie Z, Zhang Q (2022) MiR-221–3p targets HIPK2 to promote diabetic wound healing. Microvasc Res 140:104306. https://doi.org/10.1016/j.mvr.2021.104306

  79. Kim S, Lee SK, Kim H, Kim TM (2018) Exosomes secreted from induced pluripotent stem cell-derived mesenchymal stem cells accelerate skin cell proliferation. Int J Mol Sci 19(10). https://doi.org/10.3390/ijms19103119

  80. Bo Y, Yang L, Liu B, Tian G, Li C, Zhang L, Yan Y (2022) Exosomes from human induced pluripotent stem cells-derived keratinocytes accelerate burn wound healing through miR-762 mediated promotion of keratinocytes and endothelial cells migration. J Nanobiotechnology 20(1):291. https://doi.org/10.1186/s12951-022-01504-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wgealla M, Liang H, Chen R, Xie Y, Li F, Qin M, Zhang X (2022) Amniotic fluid derived stem cells promote skin regeneration and alleviate scar formation through exosomal miRNA-146a-5p via targeting CXCR4. J Cosmet Dermatol 21(10):5026–5036. https://doi.org/10.1111/jocd.14956

    Article  PubMed  Google Scholar 

  82. Balbi C, Piccoli M, Barile L, Papait A, Armirotti A, Principi E, Bollini S (2017) First characterization of human amniotic fluid stem cell extracellular vesicles as a powerful paracrine tool endowed with regenerative potential. Stem Cells Transl Med 6(5):1340–1355. https://doi.org/10.1002/sctm.16-0297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wgealla M, Liang H, Chen R, Xie Y, Li F, Qin M, Zhang X (2022) Amniotic fluid derived stem cells promote skin regeneration and alleviate scar formation through exosomal miRNA-146a-5p via targeting CXCR4. J Cosmet Dermatol. https://doi.org/10.1111/jocd.14956

    Article  PubMed  Google Scholar 

  84. Zhang D, Wei G, Li P, Zhou X, Zhang Y (2014) Urine-derived stem cells: A novel and versatile progenitor source for cell-based therapy and regenerative medicine. Genes Dis 1(1):8–17. https://doi.org/10.1016/j.gendis.2014.07.001

    Article  PubMed  PubMed Central  Google Scholar 

  85. Chen CY, Rao SS, Ren L, Hu XK, Tan YJ, Hu Y, Xie H (2018) Exosomal DMBT1 from human urine-derived stem cells facilitates diabetic wound repair by promoting angiogenesis. Theranostics 8(6):1607–1623. https://doi.org/10.7150/thno.22958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dunnwald M, Tomanek-Chalkley A, Alexandrunas D, Fishbaugh J, Bickenbach JR (2001) Isolating a pure population of epidermal stem cells for use in tissue engineering. Exp Dermatol 10(1):45–54. https://doi.org/10.1034/j.1600-0625.2001.100106.x

    Article  CAS  PubMed  Google Scholar 

  87. Redvers RP, Li A, Kaur P (2006) Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc Natl Acad Sci USA 103(35):13168–13173. https://doi.org/10.1073/pnas.0602579103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Walmsley GG, Maan ZN, Wong VW, Duscher D, Hu MS, Zielins ER, Longaker MT (2015) Scarless wound healing: chasing the holy grail. Plast Reconstr Surg 135(3):907–917. https://doi.org/10.1097/PRS.0000000000000972

  89. Wang P, Theocharidis G, Vlachos IS, Kounas K, Lobao A, Shu B,Veves A (2022) Exosomes derived from epidermal stem cells improve diabetic wound healing. J Invest Dermatol 142(9):2508–2517. https://doi.org/10.1016/j.jid.2022.01.030

  90. Duan M, Zhang Y, Zhang H, Meng Y, Qian M, Zhang G (2020) Epidermal stem cell-derived exosomes promote skin regeneration by downregulating transforming growth factor-beta1 in wound healing. Stem Cell Res Ther 11(1):452. https://doi.org/10.1186/s13287-020-01971-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jia R, Li J, Rui C, Ji H, Ding H, Lu Y, Sun L (2015) Comparative proteomic profile of the human umbilical cord blood exosomes between normal and preeclampsia pregnancies with high-resolution mass spectrometry. Cell Physiol Biochem 36(6):2299–2306. https://doi.org/10.1159/000430193

    Article  CAS  PubMed  Google Scholar 

  92. Kim S, Kim Y, Hyun YS, Choi H, Kim SY, Kim TG (2021) Exosomes from human cord blood plasma accelerate cutaneous wound healing by promoting fibroblast function, angiogenesis, and M2 macrophage differentiation. Biomater Sci 9(8):3028–3039. https://doi.org/10.1039/d0bm01801e

    Article  CAS  PubMed  Google Scholar 

  93. Hu Y, Rao SS, Wang ZX, Cao J, Tan YJ, Luo J, Xie H (2018) Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics 8(1):169–184. https://doi.org/10.7150/thno.21234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhao D, Yu Z, Li Y, Wang Y, Li Q, Han D (2020) GelMA combined with sustained release of HUVECs derived exosomes for promoting cutaneous wound healing and facilitating skin regeneration. J Mol Histol 51(3):251–263. https://doi.org/10.1007/s10735-020-09877-6

    Article  CAS  PubMed  Google Scholar 

  95. Yuan M, Liu K, Jiang T, Li S, Chen J, Wu Z, Chen Z (2022) GelMA/PEGDA microneedles patch loaded with HUVECs-derived exosomes and Tazarotene promote diabetic wound healing. J Nanobiotechnology 20(1):147. https://doi.org/10.1186/s12951-022-01354-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang Q, Lai D (2020) Application of human amniotic epithelial cells in regenerative medicine: a systematic review. Stem Cell Res Ther 11(1):439. https://doi.org/10.1186/s13287-020-01951-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Farhadihosseinabadi B, Farahani M, Tayebi T, Jafari A, Biniazan F, Modaresifar K, Niknejad H (2018) Amniotic membrane and its epithelial and mesenchymal stem cells as an appropriate source for skin tissue engineering and regenerative medicine. Artif Cells Nanomed Biotechnol 46(sup2):431–440. https://doi.org/10.1080/21691401.2018.1458730

  98. Zhao B, Wu GF, Zhang YJ, Zhang W, Yang FF, Xiao D, Hu DH (2017) Effects of human amniotic epithelial stem cells-derived exosomes on healing of wound with full-thickness skin defect in rats. Zhonghua Shao Shang Za Zhi 33(1):18–23. https://doi.org/10.3760/cma.j.issn.1009-2587.2017.01.005

    Article  CAS  PubMed  Google Scholar 

  99. Zhao B, Zhang Y, Han S, Zhang W, Zhou Q, Guan H, Hu D (2017) Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation. J Mol Histol 48(2):121–132. https://doi.org/10.1007/s10735-017-9711-x

    Article  CAS  PubMed  Google Scholar 

  100. Wei P, Zhong C, Yang X, Shu F, Xiao S, Gong T, Xia Z (2020) Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function. Burns Trauma 8:tkaa020. https://doi.org/10.1093/burnst/tkaa020

  101. Landen NX, Li D, Stahle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73(20):3861–3885. https://doi.org/10.1007/s00018-016-2268-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Li M, Wang T, Tian H, Wei G, Zhao L, Shi Y (2019) Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model. Artif Cells Nanomed Biotechnol 47(1):3793–3803. https://doi.org/10.1080/21691401.2019.1669617

    Article  CAS  PubMed  Google Scholar 

  103. Kim H, Wang SY, Kwak G, Yang Y, Kwon IC, Kim SH (2019) Exosome-guided phenotypic switch of M1 to M2 macrophages for cutaneous wound healing. Adv Sci (Weinh) 6(20):1900513. https://doi.org/10.1002/advs.201900513

    Article  CAS  PubMed  Google Scholar 

  104. Han X, Wu P, Li L, Sahal HM, Ji C, Zhang J, Xu W (2021) Exosomes derived from autologous dermal fibroblasts promote diabetic cutaneous wound healing through the Akt/beta-catenin pathway. Cell Cycle 20(5–6):616–629. https://doi.org/10.1080/15384101.2021.1894813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Thulabandu V, Chen D, Atit RP (2018) Dermal fibroblast in cutaneous development and healing. Wiley Interdiscip Rev Dev Biol 7(2). https://doi.org/10.1002/wdev.307

  106. Chen L, Qin L, Chen C, Hu Q, Wang J, Shen J (2021) Serum exosomes accelerate diabetic wound healing by promoting angiogenesis and ECM formation. Cell Biol Int 45(9):1976–1985. https://doi.org/10.1002/cbin.11627

    Article  CAS  PubMed  Google Scholar 

  107. Li Y, Yu Y, Xie Z, Ye X, Liu X, Xu B, Mao J (2021) Serum-derived exosomes accelerate scald wound healing in mice by optimizing cellular functions and promoting Akt phosphorylation. Biotechnol Lett 43(8):1675–1684. https://doi.org/10.1007/s10529-021-03148-4

    Article  CAS  PubMed  Google Scholar 

  108. Han Y, Jia L, Zheng Y, Li W (2018) Salivary exosomes: emerging roles in systemic disease. Int J Biol Sci 14(6):633–643. https://doi.org/10.7150/ijbs.25018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Liu M, Liu Z, Chen Y, Peng S, Yang J, Chen C, He W (2022) Dendritic epidermal T cells secreting exosomes promote the proliferation of epidermal stem cells to enhance wound re-epithelialization. Stem Cell Res Ther 13(1):121. https://doi.org/10.1186/s13287-022-02783-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Geiger A, Walker A, Nissen E (2015) Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice. Biochem Biophys Res Commun 467(2):303–309. https://doi.org/10.1016/j.bbrc.2015.09.166

    Article  CAS  PubMed  Google Scholar 

  111. Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B, Qian H (2018) Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving beta-cell destruction. ACS Nano 12(8):7613–7628. https://doi.org/10.1021/acsnano.7b07643

    Article  CAS  PubMed  Google Scholar 

  112. Man K, Brunet MY, Jones MC, Cox SC (2020) Engineered extracellular vesicles: tailored-made nanomaterials for medical applications. Nanomaterials (Basel) 10(9). https://doi.org/10.3390/nano10091838

  113. Zhang Y, Bi J, Huang J, Tang Y, Du S, Li P (2020) Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine 15:6917–6934. https://doi.org/10.2147/IJN.S264498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jahangir MA, Khan R, Sarim Imam S (2018) Formulation of sitagliptin-loaded oral polymeric nano scaffold: process parameters evaluation and enhanced anti-diabetic performance. Artif Cells Nanomed Biotechnol 46(sup1):66–78. https://doi.org/10.1080/21691401.2017.1411933

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by Nantong Grant from the Key special science and technology plan projects of COVID-19 for People's livelihood (No. H202136).

Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China

    Lei Yu, Zihao Dai, Tingting Zhang & Yunjuan Gu

  2. Department of Histology and Embryology, Medical School, Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China

    Jianxin Qin, Jiajun Xing & Xia Chen

  3. Nantong Xingzhong Cell Engineering Co. LTD, Nantong, Jiangsu, 226001, People’s Republic of China

    Feng Wang & Jin Zhou

  4. Department of Respiratory Medicine, Nantong Third People’s Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, China

    Xiaobai Zhang

Authors
  1. Lei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianxin Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiajun Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zihao Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tingting Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaobai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yunjuan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the review. All authors were involved in literature search and writing of the manuscript.

Corresponding authors

Correspondence to Xia Chen or Yunjuan Gu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read and agreed to the submitted version of the manuscript.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Lei Yu, Jianxin Qin, and Jiajun Xing contributed equally to this work.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, L., Qin, J., Xing, J. et al. The mechanisms of exosomes in diabetic foot ulcers healing: a detailed review. J Mol Med 101, 1209–1228 (2023). https://doi.org/10.1007/s00109-023-02357-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-023-02357-w

Keywords

Search

Navigation