Extracellular vesicles modulate key signalling pathways in refractory wound healing

Bowen Yang; Yumeng Lin; Yibo Huang; Nanxi Zhu; Ying-Qiang Shen

doi:10.1093/burnst/tkad039

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Extracellular vesicles modulate key signalling pathways in refractory wound healing

更新时间：2024-02-04

- Extracellular vesicles modulate key signalling pathways in refractory wound healing
- Extracellular vesicles modulate key signalling pathways in refractory wound healing
- Burns & Trauma 2023年11卷第1期
- 作者机构：
  
  1. State Key Laboratory of Oral Diseases
  2. Sichuan University
- 作者简介：
- 基金信息：
- DOI：10.1093/burnst/tkad039
  中图分类号：
- 纸质出版日期：2023，
  
  网络出版日期：2023-11-16，
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Bowen Yang, Yumeng Lin, Yibo Huang, 等. Extracellular vesicles modulate key signalling pathways in refractory wound healing[J]. Burns & Trauma, 2023,11(1).

Bowen Yang, Yumeng Lin, Yibo Huang, Nanxi Zhu, Ying-Qiang Shen, Extracellular vesicles modulate key signalling pathways in refractory wound healing, Burns & Trauma, Volume 11, 2023, tkad039, https://doi.org/10.1093/burnst/tkad039
Bowen Yang, Yumeng Lin, Yibo Huang, 等. Extracellular vesicles modulate key signalling pathways in refractory wound healing[J]. Burns & Trauma, 2023,11(1). DOI： 10.1093/burnst/tkad039.

Bowen Yang, Yumeng Lin, Yibo Huang, Nanxi Zhu, Ying-Qiang Shen, Extracellular vesicles modulate key signalling pathways in refractory wound healing, Burns & Trauma, Volume 11, 2023, tkad039, https://doi.org/10.1093/burnst/tkad039 DOI：

摘要

Abstract

Chronic wounds are wounds that cannot heal properly due to various factors

such as underlying diseases

infection or reinjury

and improper healing of skin wounds and ulcers can cause a serious economic burden. Numerous studies have shown that extracellular vesicles (EVs) derived from stem/progenitor cells promote wound healing

reduce scar formation and have significant advantages over traditional treatment methods. EVs are membranous particles that carry various bioactive molecules from their cellular origins

such as cytokines

nucleic acids

enzymes

lipids and proteins. EVs can mediate cell-to-cell communication and modulate various physiological processes

such as cell differentiation

angiogenesis

immune response and tissue remodelling. In this review

we summarize the recent advances in EV-based wound healing

focusing on the signalling pathways that are regulated by EVs and their cargos. We discuss how EVs derived from different types of stem/progenitor cells can promote wound healing and reduce scar formation by modulating the Wnt/β-catenin

phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin

vascular endothelial growth factor

transforming growth factor β and JAK–STAT pathways. Moreover

we also highlight the challenges and opportunities for engineering or modifying EVs to enhance their efficacy and specificity for wound healing.

关键词

Keywords

Extracellular vesiclesRefractory woundStem/progenitor cellsScar formationEngineered extracellular vesiclesWound healingScarSignalling pathway

references

1.Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2019;99:665–706. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30475656. https://doi.org/10.1152/physrev.00067.2017.

2.Sun J, Hua B, Livingston EW, Taves S, Johansen PB, Hoffman M, et al. Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis. Blood. 2017;129:2161–71. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28039188. https://doi.org/10.1182/blood-2016-08-734053.

3.Aragona M, Dekoninck S, Rulands S, Lenglez S, Mascre G, Simons BD, et al. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat Commun. 2017;8:14684. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28248284. https://doi.org/10.1038/ncomms14684.

4.Wound Care Market Size. Share & COVID-19 lmpact analysis, by type(advanced wound dressing,(antimicrobial dressings，alginate Dressings,Foam dressings，hydrocolloid dressings, and others)，traditional WoundCare products, negative pressure wound therapy, bioactives (biological SkinEquivalents，growth Factors,and others),and others);by application(chronic wounds (diabetic foot Ulcers,Pressure Ulcers,leg Ulcers,andothers), and acute wounds (surgical Wounds,and others)); by end user(hospitals, Clinics,Homecare settings, and others), and regional forecast, 2022-2029. Market Research Report. 2022; 242. Retrieved from; https://www.fortunebusinessinsights.com/wound-care-market-103268.

5.Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6:265sr266 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25473038.

6.Chen CY, Yin H, Chen X, Chen TH, Liu HM, Rao SS, et al. Angstrom-scale silver particle-embedded carbomer gel promotes wound healing by inhibiting bacterial colonization and inflammation. Sci Adv. 2020;6(43). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/33097529.

7.Gimblet C, Meisel JS, Loesche MA, Cole SD, Horwinski J, Novais FO, et al. Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation. Cell Host Microbe. 2017;22:13–24 e14. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28669672.

8.Bonora BM, Cappellari R, Mazzucato M, Rigato M, Grasso M, Menegolo M, et al. Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: a phase IIa, randomized, double-blind, placebo-controlled trial. Stem Cells Transl Med. 2020;9:965–73. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32485785.

9.Pang Q, Lou D, Li S, Wang G, Qiao B, Dong S, et al. Smart flexible electronics-integrated wound dressing for real-time monitoring and on-demand treatment of infected wounds. Adv Sci (Weinh). 2020;7:1902673. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32195091.

10.Heun Y, Pogoda K, Anton M, Pircher J, Pfeifer A, Woernle M, et al. HIF-1alpha dependent wound healing angiogenesis in vivo can be controlled by site-specific Lentiviral magnetic targeting of SHP-2. Mol Ther. 2017;25:1616–27. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28434868.

11.Hiragami F, Motoda H, Takezawa T, Takabayashi C, Inoue S, Wakatake Y, et al. Heat shock-induced three-dimensional-like proliferation of normal human fibroblasts mediated by pressed silk. Int J Mol Sci. 2009;10:4963–76. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20087471.

12.Srifa W, Kosaric N, Amorin A, Jadi O, Park Y, Mantri S, et al. Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice. Nat Commun. 2020;11:2470. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32424320.

13.Costa ML, Achten J, Bruce J, Tutton E, Petrou S, Lamb SE, et al. Effect of negative pressure wound therapy vs standard wound management on 12-month disability among adults with severe open fracture of the lower limb: the WOLLF randomized clinical trial. JAMA. 2018;319:2280–8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29896626.

14.McKenzie K, Fingerhut L, Walker S, Harrison A, Harrison JE. Classifying external causes of injury: history, current approaches, and future directions. Epidemiol Rev. 2012;34:4–16. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22045696.

15.Wei, J. J., Kim, H. S., Spencer, C. A., Brennan-Crispi, D., Zheng, Y., Johnson, N. M., et al. , Activation of TRPA1 nociceptor promotes systemic adult mammalian skin regeneration, Sci Immunol, 2020, 5(50). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32859683. https://doi.org/10.1126/sciimmunol.aba5683.

16.Tan JL, Lau SN, Leaw B, Nguyen HPT, Salamonsen LA, Saad MI, et al. Amnion epithelial cell-derived exosomes restrict lung injury and enhance endogenous lung repair. Stem Cells Transl Med. 2018;7:180–96. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29297621.

17.Whittaker TE, Nagelkerke A, Nele V, Kauscher U, Stevens MM. Experimental artefacts can lead to misattribution of bioactivity from soluble mesenchymal stem cell paracrine factors to extracellular vesicles. J Extracell Vesicles. 2020;9:1807674. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32944192.

18.Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/32029601. https://doi.org/10.1126/science.aau6977.

19.Zhu J, Zhang M, Gao Y, Qin X, Zhang T, Cui W, et al. Tetrahedral framework nucleic acids promote scarless healing of cutaneous wounds via the AKT-signaling pathway. Signal Transduct Target Ther. 2020;5:120. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32678073.

20.Han Z, Liu S, Pei Y, Ding Z, Li Y, Wang X, et al. Highly efficient magnetic labelling allows MRI tracking of the homing of stem cell-derived extracellular vesicles following systemic delivery. J Extracell Vesicles. 2021;10(3):e12054 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33489014..

21.Kim H, Lee JW, Han G, Kim K, Yang Y, Kim SH. Extracellular vesicles as potential Theranostic platforms for skin diseases and aging. Pharmaceutics. 2021;13(5). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/34065468. https://doi.org/10.3390/pharmaceutics13050760.

22.Pardo F, Villalobos-Labra R, Sobrevia B, Toledo F, Sobrevia L. Extracellular vesicles in obesity and diabetes mellitus. Mol Asp Med. 2018;60:81–91. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29175307.

23.Cheng L, Hill AF. Therapeutically harnessing extracellular vesicles. Nat Rev Drug Discov. 2022;21:379–99. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35236964.

24.Mills EW, Green R, Ingolia NT. Slowed decay of mRNAs enhances platelet specific translation. Blood. 2017;129:e38–48. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28213379.

25.Lienemann PS, Vallmajo-Martin Q, Papageorgiou P, Blache U, Metzger S, Kivelio AS, et al. Smart hydrogels for the augmentation of bone regeneration by endogenous mesenchymal progenitor cell recruitment. Adv Sci (Weinh). 2020;7:1903395. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32274319.

26.Beck IM, Vanden Berghe W, Vermeulen L, Yamamoto KR, Haegeman G, De Bosscher K. Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr Rev. 2009;30:830–82. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19890091.

27.Kourtzelis I, Li X, Mitroulis I, Grosser D, Kajikawa T, Wang B, et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol. 2019;20:40–9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30455459.

28.Hahm E, Li J, Kim K, Huh S, Rogelj S, Cho J. Extracellular protein disulfide isomerase regulates ligand-binding activity of alphaMbeta2 integrin and neutrophil recruitment during vascular inflammation. Blood. 2013;121:3789–800S3781-3715 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23460613..

29.Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiol Rev. 2019;99:1325–80. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30920354.

30.Baker RG, Hayden MS, Ghosh S. NF-kappaB, inflammation, and metabolic disease. Cell Metab. 2011;13:11–22. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21195345.

31.Chow NA, Jasenosky LD, Goldfeld AE. A distal locus element mediates IFN-gamma priming of lipopolysaccharide-stimulated TNF gene expression. Cell Rep. 2014;9:1718–28. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25482561.

32.Li X, Liu R, Su X, Pan Y, Han X, Shao C, et al. Harnessing tumor-associated macrophages as aids for cancer immunotherapy. Mol Cancer. 2019;18:177. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31805946.

33.Liu X, Xu J, Zhang B, Liu J, Liang C, Meng Q, et al. The reciprocal regulation between host tissue and immune cells in pancreatic ductal adenocarcinoma: new insights and therapeutic implications. Mol Cancer. 2019;18:184. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31831007.

34.Wang SY, Kim H, Kwak G, Yoon HY, Jo SD, Lee JE, et al. Development of biocompatible HA hydrogels embedded with a new synthetic peptide promoting cellular migration for advanced wound care management. Adv Sci (Weinh). 2018;5:1800852. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30479928.

35.Liu B, Xia X, Zhu F, Park E, Carbajal S, Kiguchi K, et al. IKKalpha is required to maintain skin homeostasis and prevent skin cancer. Cancer Cell. 2008;14:212–25. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18772111.

36.Lang E, Polec A, Lang A, Valk M, Blicher P, Rowe AD, et al. Coordinated collective migration and asymmetric cell division in confluent human keratinocytes without wounding. Nat Commun. 2018;9:3665. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30202009.

37.Deng CC, Hu YF, Zhu DH, Cheng Q, Gu JJ, Feng QL, et al. Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases. Nat Commun. 2021;12:3709. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34140509.

38.Hoyle NP, Seinkmane E, Putker M, Feeney KA, Krogager TP, Chesham JE, et al. Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing. Sci Transl Med. 2017;8(415). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/29118260. https://doi.org/10.1126/scitranslmed.aal2774.

39.Lin X, Tang F, Jiang S, Khamis H, Bongers A, Whitelock JM, et al. A biomimetic approach toward enhancing angiogenesis: Recombinantly expressed domain V of human Perlecan is a bioactive molecule that promotes angiogenesis and vascularization of implanted biomaterials. Adv Sci (Weinh). 2020;7:2000900. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32995122.

40.Lee TH, Yeh CF, Lee YT, Shih YC, Chen YT, Hung CT, et al. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFbeta signaling through TGFBR1 stabilization. Nat Commun. 2020;11:4254. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32848143.

41.Slaby O, Svoboda M, Michalek J, Vyzula R. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009;8:102. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19912656.

42.Yuge S, Nishiyama K, Arima Y, Hanada Y, Oguri-Nakamura E, Hanada S, et al. Mechanical loading of intraluminal pressure mediates wound angiogenesis by regulating the TOCA family of F-BAR proteins. Nat Commun. 2022;13:2594. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35551172.

43.Xu L, Stevens J, Hilton MB, Seaman S, Conrads TP, Veenstra TD, et al. COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models. Sci Transl Med. 2014;6:242ra284. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24964992.

44.Ueki R, Uchida S, Kanda N, Yamada N, Ueki A, Akiyama M, et al. A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application. Sci Adv. 2020;6:eaay2801. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32270033.

45.Hanna A, Shevde LA. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol Cancer. 2016;15:24. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26988232.

46.John AE, Graves RH, Pun KT, Vitulli G, Forty EJ, Mercer PF, et al. Translational pharmacology of an inhaled small molecule alphavbeta6 integrin inhibitor for idiopathic pulmonary fibrosis. Nat Commun. 2020;11:4659. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32938936.

47.Bozic M, Caus M, Rodrigues-Diez RR, Pedraza N, Ruiz-Ortega M, Gari E, et al. Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis. Nat Commun. 2020;11:1943. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32327648.

48.Maller O, Drain AP, Barrett AS, Borgquist S, Ruffell B, Zakharevich I, et al. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat Mater. 2021;20:548–59. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33257795.

49.van Nieuwenhoven FA, Turner NA. The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction. Vasc Pharmacol. 2013;58:182–8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22885638.

50.Zhao R, Liang H, Clarke E, Jackson C, Xue M. Inflammation in chronic wounds. Int J Mol Sci. 2016;17(12). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/27973441. https://doi.org/10.3390/ijms17122085.

51.Kobayashi T, Liu X, Kim HJ, Kohyama T, Wen FQ, Abe S, et al. TGF-beta1 and serum both stimulate contraction but differentially affect apoptosis in 3D collagen gels. Respir Res. 2005;6:141. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16324212.

52.Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–16. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17525249.

53.Lu Y, Wen H, Huang J, Liao P, Liao H, Tu J, et al. Extracellular vesicle-enclosed miR-486-5p mediates wound healing with adipose-derived stem cells by promoting angiogenesis. J Cell Mol Med. 2020;24:9590–604. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32666704.

54.Babaei M, Rezaie J. Application of stem cell-derived exosomes in ischemic diseases: opportunity and limitations. J Transl Med. 2021;19:196. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33964940.

55.Harding KG, Morris HL, Patel GK. Science, medicine and the future: healing chronic wounds. BMJ. 2002;324:160–3. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11799036.

56.Bellu, E., Medici, S., Coradduzza, D., Cruciani, S., Amler, E., & Maioli, M., Nanomaterials in skin regeneration and rejuvenation, Int J Mol Sci, 2021, 22(13). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34209468. https://doi.org/10.3390/ijms22137095.

57.Bice BD, Stephens MR, Georges SJ, Venancio AR, Bermant PC, Warncke AV, et al. Environmental enrichment induces Pericyte and IgA-dependent wound repair and lifespan extension in a colon tumor model. Cell Rep. 2017;19:760–73. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28445727.

58.Ruggeri M, Bianchi E, Rossi S, Vigani B, Bonferoni MC, Caramella C, et al. Nanotechnology-based medical devices for the treatment of chronic skin lesions: from research to the clinic. Pharmaceutics. 2020;12(9). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/32867241. https://doi.org/10.3390/pharmaceutics12090815.

59.Toutous Trellu L, Nkemenang P, Comte E, Ehounou G, Atangana P, Mboua DJ, et al. Differential diagnosis of skin ulcers in a mycobacterium ulcerans endemic area: data from a prospective study in Cameroon. PLoS Negl Trop Dis. 2016;10(4):e0004385. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/27074157.

60.Bansal A, Schmidt M, Rennegarbe M, Haupt C, Liberta F, Stecher S, et al. AA amyloid fibrils from diseased tissue are structurally different from in vitro formed SAA fibrils. Nat Commun. 2021;12:1013. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33579941.

61.Miner JJ, Xia L, Yago T, Kappelmayer J, Liu Z, Klopocki AG, et al. Separable requirements for cytoplasmic domain of PSGL-1 in leukocyte rolling and signaling under flow. Blood. 2008;112:2035–45. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18550846.

62.Michel P, Granica S, Magiera A, Rosinska K, Jurek M, Poraj L, et al. Salicylate and Procyanidin-rich stem extracts of Gaultheria procumbens L. inhibit pro-inflammatory enzymes and suppress pro-inflammatory and pro-oxidant functions of human neutrophils ex vivo. Int J Mol Sci. 2019;20(7). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/30970662.

63.Evans MA, Smart N, Dube KN, Bollini S, Clark JE, Evans HG, et al. Thymosin beta4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing. Nat Commun. 2013;4:2081. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23820300.

64.Jiang D, Christ S, Correa-Gallegos D, Ramesh P, Kalgudde Gopal S, Wannemacher J, et al. Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin. Nat Commun. 2020;11:5653. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33159076.

65.American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:S62–9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20042775.

66.Hu W, Liu C, Bi ZY, Zhou Q, Zhang H, Li LL, et al. Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology. Mol Cancer. 2020;19:102. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32503543.

67.Zhu M, Chu Y, Shang Q, Zheng Z, Li Y, Cao L, et al. Mesenchymal stromal cells pretreated with pro-inflammatory cytokines promote skin wound healing through VEGFC-mediated angiogenesis. Stem Cells Transl Med. 2020;9:1218–32 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32534464.

68.Sebastiano V, Zhen HH, Haddad B, Bashkirova E, Melo SP, Wang P, et al. Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa. Sci Transl Med. 2014;6:264ra163. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25429056.

69.Chen SH, Chou PY, Chen ZY, Lin FH. Electrospun water-borne polyurethane Nanofibrous membrane as a barrier for preventing postoperative Peritendinous adhesion. Int J Mol Sci. 2019;20(7). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/30939838. https://doi.org/10.3390/ijms20071625.

70.Sun Z, Yang S, Zhou Q, Wang G, Song J, Li Z, et al. Emerging role of exosome-derived long non-coding RNAs in tumor microenvironment. Mol Cancer. 2018;17:82. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29678180.

71.Yanatori I, Richardson DR, Dhekne HS, Toyokuni S, Kishi F. CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Blood. 2021;138:1490–503. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34265052.

72.Feng Q, Luo Y, Zhang XN, Yang XF, Hong XY, Sun DS, et al. MAPT/tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: a vicious cycle in Alzheimer neurodegeneration. Autophagy. 2020;16:641–58. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31223056.

73.Hofmann K, Tomiuk S, Wolff G, Stoffel W. Cloning and characterization of the mammalian brain-specific, Mg2+−dependent neutral sphingomyelinase. Proc Natl Acad Sci U S A. 2000;97:5895–900. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10823942.

74.Janockova J, Slovinska L, Harvanova D, Spakova T, Rosocha J. New therapeutic approaches of mesenchymal stem cells-derived exosomes. J Biomed Sci. 2021;28:39. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34030679.

75.Sung BH, von Lersner A, Guerrero J, Krystofiak ES, Inman D, Pelletier R, et al. A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells. Nat Commun. 2020;11:2092. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32350252.

76.Gupta A, Pulliam L. Exosomes as mediators of neuroinflammation. J Neuroinflammation. 2014;11:68. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24694258.

77.Giaccia AJ. Molecular radiobiology: the state of the art. J Clin Oncol. 2014;32:2871–8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25113768.

78.French KC, Antonyak MA, Cerione RA. Extracellular vesicle docking at the cellular port: extracellular vesicle binding and uptake. Semin Cell Dev Biol. 2017;67:48–55. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28104520.

79.Wendler F, Bota-Rabassedas N, Franch-Marro X. Cancer becomes wasteful: emerging roles of exosomes(dagger) in cell-fate determination. J Extracell Vesicles. 2013;2; Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24223259.

80.Kumar R, Tang Q, Muller SA, Gao P, Mahlstedt D, Zampagni S, et al. Fibroblast growth factor 2-mediated regulation of neuronal exosome release depends on VAMP3/Cellubrevin in hippocampal neurons. Adv Sci (Weinh). 2020;7:1902372 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32195080.

81.Iraci N, Gaude E, Leonardi T, Costa ASH, Cossetti C, Peruzzotti-Jametti L, et al. Extracellular vesicles are independent metabolic units with asparaginase activity. Nat Chem Biol. 2017;13:951–5. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28671681.

82.Tai YL, Chu PY, Lee BH, Chen KC, Yang CY, Kuo WH, et al. Basics and applications of tumor-derived extracellular vesicles. J Biomed Sci. 2019;26:35. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31078138.

83.Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017;27:172–88. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27979573.

84.Tao SC, Guo SC, Zhang CQ. Modularized extracellular vesicles: the Dawn of prospective personalized and precision medicine. Adv Sci (Weinh). 2018;5:1700449. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29619297.

85.Chase LG, Yang S, Zachar V, Yang Z, Lakshmipathy U, Bradford J, et al. Development and characterization of a clinically compliant xeno-free culture medium in good manufacturing practice for human multipotent mesenchymal stem cells. Stem Cells Transl Med. 2012;1:750–8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23197667.

86.Yoshida K, Nakashima A, Doi S, Ueno T, Okubo T, Kawano KI, et al. Serum-free medium enhances the immunosuppressive and Antifibrotic abilities of mesenchymal stem cells utilized in experimental renal fibrosis. Stem Cells Transl Med. 2018;7:893–905. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30269426.

87.Maldonado-Lasuncion I, O'Neill N, Umland O, Verhaagen J, Oudega M. Macrophage-derived inflammation induces a transcriptome makeover in mesenchymal stromal cells enhancing their potential for tissue repair. Int J Mol Sci. 2021;22(2). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/33466704. https://doi.org/10.3390/ijms22020781.

88.Al-Dossary AA, Tawfik EA, Isichei AC, Sun X, Li J, Alshehri AA, et al. Engineered EV-mimetic nanoparticles as therapeutic delivery vehicles for high-grade serous ovarian cancer. Cancers (Basel). 2021;13(12). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/34203051. https://doi.org/10.3390/cancers13123075.

89.Lee H, Li C, Zhang Y, Zhang D, Otterbein LE, Jin Y. Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli. J Exp Med. 2019;216:2202–20. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31235510.

90.Men Y, Yelick J, Jin S, Tian Y, Chiang MSR, Higashimori H, et al. Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS. Nat Commun. 2019;10:4136. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31515491.

91.Pomatto M, Gai C, Negro F, Cedrino M, Grange C, Ceccotti E, et al. Differential therapeutic effect of extracellular vesicles derived by bone marrow and adipose mesenchymal stem cells on wound healing of diabetic ulcers and correlation to their cargoes. Int J Mol Sci. 2021;22(8). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/33917759. https://doi.org/10.3390/ijms22083851.

92.Yoshioka Y, Konishi Y, Kosaka N, Katsuda T, Kato T, Ochiya T. Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles. 2013;2. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24009892.

93.Xie C, Ji N, Tang Z, Li J, Chen Q. The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers. Mol Cancer. 2019;18:83. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30954079.

94.Chen SY, Lin MC, Tsai JS, He PL, Luo WT, Herschman H, et al. EP4 antagonist-elicited extracellular vesicles from mesenchymal stem cells rescue cognition/learning deficiencies by restoring brain cellular functions. Stem Cells Transl Med. 2019;8:707–23. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30891948.

95.de Kerckhove M, Tanaka K, Umehara T, Okamoto M, Kanematsu S, Hayashi H, et al. Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds. EMBO Mol Med. 2018;10(10). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/30171089. https://doi.org/10.15252/emmm.201809024.

96.Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B. 2016;6:287–96. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27471669.

97.Bjorge IM, Kim SY, Mano JF, Kalionis B, Chrzanowski W. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine - a new paradigm for tissue repair. Biomater Sci. 2017;6:60–78. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29184934.

98.Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 2013;17:745–55. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23623748.

99.Arenas DJ, Floess K, Kobrin D, Pai RL, Srkalovic MB, Tamakloe MA, et al. Increased mTOR activation in idiopathic multicentric Castleman disease. Blood. 2020;135:1673–84. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32206779.

100.Wang C, Dai X, Wu S, Xu W, Song P, Huang K. FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis. Nat Commun. 2021;12:2616. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33972548.

101.Yaeger R, Corcoran RB. Targeting alterations in the RAF-MEK pathway. Cancer Discov. 2019;9:329–41. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30770389.

102.Fan Y, Bergmann A. Apoptosis-induced compensatory proliferation. The cell is dead. Long live the cell! Trends Cell Biol. 2008;18:467–73. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18774295.

103.Yuan S, Chu H, Huang J, Zhao X, Ye ZW, Lai PM, et al. Viruses harness YxxO motif to interact with host AP2M1 for replication: a vulnerable broad-spectrum antiviral target. Sci Adv. 2020;6:eaba7910. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32923629.

104.Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34980884.

105.Ma L, Chen C, Liu D, Huang Z, Li J, Liu H, et al. Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair. Bioact Mater. 2023;19:626–41. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35600968.

106.Lou P, Liu S, Xu X, Pan C, Lu Y, Liu J. Extracellular vesicle-based therapeutics for the regeneration of chronic wounds: current knowledge and future perspectives. Acta Biomater. 2021;119:42–56. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33161186.

107.Zhang B, Shi Y, Gong A, Pan Z, Shi H, Yang H, et al. HucMSC exosome-delivered 14-3-3zeta orchestrates self-control of the Wnt response via modulation of YAP during cutaneous regeneration. Stem Cells. 2016;34:2485–500. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27334574.

108.Wei Q, Wang Y, Ma K, Li Q, Li B, Hu W, et al. Extracellular vesicles from human umbilical cord mesenchymal stem cells facilitate diabetic wound healing through MiR-17-5p-mediated enhancement of angiogenesis. Stem Cell Rev Rep. 2022;18:1025–40. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33942217.

109.Qian L, Pi L, Fang BR, Meng XX. Adipose mesenchymal stem cell-derived exosomes accelerate skin wound healing via the lncRNA H19/miR-19b/SOX9 axis. Lab Investig. 2021;101:1254–66. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34045678.

110.Li C, An Y, Sun Y, Yang F, Xu Q, Wang Z. Adipose mesenchymal stem cell-derived exosomes promote wound healing through the WNT/beta-catenin Signaling pathway in dermal fibroblasts. Stem Cell Rev Rep. 2022;18:2059–73. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35471485.

111.Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020;18:449. Retrieved from .https://www.ncbi.nlm.nih.gov/pubmed/33246476.

112.Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 2007;13:7003–11. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18056176.

113.Akcora BO, Storm G, Bansal R. Inhibition of canonical WNT signaling pathway by beta-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12. Biochim Biophys Acta Mol basis Dis. 2018;1864:804–18. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29217140.

114.Xu P, Xin Y, Zhang Z, Zou X, Xue K, Zhang H, et al. Extracellular vesicles from adipose-derived stem cells ameliorate ultraviolet B-induced skin photoaging by attenuating reactive oxygen species production and inflammation. Stem Cell Res Ther. 2020;11:264. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32611371.

115.Wu P, Zhang B, Shi H, Qian H, Xu W. MSC-exosome: a novel cell-free therapy for cutaneous regeneration. Cytotherapy. 2018;20:291–301. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29434006.

116.Dovrat S, Caspi M, Zilberberg A, Lahav L, Firsow A, Gur H, et al. 14-3-3 and beta-catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway. Mol Oncol. 2014;8:894–911. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24721736.

117.Deng F, Peng L, Li Z, Tan G, Liang E, Chen S, et al. YAP triggers the Wnt/beta-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury. Cell Death Dis. 2018;9:153. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29396428.

118.Jere SW, Houreld NN, Abrahamse H. Role of the PI3K/AKT (mTOR and GSK3beta) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 2019;50:52–9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30890300.

119.Castilho RM, Squarize CH, Gutkind JS. Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing. Oral Dis. 2013;19:551–8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23379329.

120.Acosta-Martinez M, Cabail MZ. The PI3K/Akt pathway in meta-inflammation. Int J Mol Sci. 2022;23(23). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/36499659.

121.Xue JF, Shi ZM, Zou J, Li XL. Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis. Biomed Pharmacother. 2017;89:1252–61. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28320092.

122.Wang J, Lv X, Guo X, Dong Y, Peng P, Huang F, et al. Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells. Oncogene. 2021;10:8. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/33431808.

123.Martin M, Schifferle RE, Cuesta N, Vogel SN, Katz J, Michalek SM. Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. J Immunol. 2003;171:717–25. Retrieved from .https://www.ncbi.nlm.nih.gov/pubmed/12847238.

124.Campos A, Sharma S, Obermair A, Salomon C. Extracellular vesicle-associated miRNAs and Chemoresistance: a systematic review. Cancers (Basel). 2021;13(18). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/34572835. https://doi.org/10.3390/cancers13184608.

125.Li L, Wang H, Zhang J, Chen X, Zhang Z, Li Q. Effect of endothelial progenitor cell-derived extracellular vesicles on endothelial cell ferroptosis and atherosclerotic vascular endothelial injury. Cell Death Discov. 2021;7:235. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34493702.

126.Ma Y, Zhou D, Zhang H, Tang L, Qian F, Su J. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote the proliferation of Schwann cells by regulating the PI3K/AKT Signaling pathway via transferring miR-21. Stem Cells Int. 2021;2021:1496101. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34552631.

127.Hu S, Wang Z, Jin C, Chen Q, Fang Y, Jin J, et al. Human amniotic epithelial cell-derived extracellular vesicles provide an extracellular matrix-based microenvironment for corneal injury repair. J Tissue Eng. 2022;13:20417314221122123. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/36093432.

128.Sohrabi B, Dayeri B, Zahedi E, Khoshbakht S, Nezamabadi Pour N, Ranjbar H, et al. Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy. Cancer Gene Ther. 2022;29:1105–16. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35082400.

129.Li G, Wang B, Ding X, Zhang X, Tang J, Lin H. Plasma extracellular vesicle delivery of miR-210-3p by targeting ATG7 to promote sepsis-induced acute lung injury by regulating autophagy and activating inflammation. Exp Mol Med. 2021;53:1180–91. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34321587.

130.Hu Y, Zai H, Jiang W, Yao Y, Ou Z, Zhu Q. miR-126 in extracellular vesicles derived from Hepatoblastoma cells promotes the tumorigenesis of Hepatoblastoma through inducing the differentiation of BMSCs into cancer stem cells. J Immunol Res. 2021;2021:6744715. Retrieved from . https://www.ncbi.nlm.nih.gov/pubmed/34746322.

131.Furth N, Aylon Y. The LATS1 and LATS2 tumor suppressors: beyond the hippo pathway. Cell Death Differ. 2017;24:1488–501. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28644436.

132.Mana-Capelli S, McCollum D. Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote hippo signaling. J Biol Chem. 2018;293:18230–41. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30266805.

133.Li K, Yan G, Huang H, Zheng M, Ma K, Cui X, et al. Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages. J Nanobiotechnology. 2022;20:38. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35057811.

134.Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, et al. Exosome derived from human umbilical cord mesenchymal stem cell mediates MiR-181c attenuating burn-induced excessive inflammation. EBioMedicine. 2016;8:72–82. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27428420.

135.Ding Y, Bi L, Wang J. MiR-1180 promotes cardiomyocyte cell cycle re-entry after injury through the NKIRAS2-NFkappaB pathway. Biochem Cell Biol. 2020;98:449–57. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31955591.

136.Mayr, C., Hemann, M. T., & Bartel, D. P., Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation, Science, 2007, 315, 1576–9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17322030. https://doi.org/10.1126/science.1137999.

137.Zhang L, Li YJ, Wu XY, Hong Z, Wei WS. MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose-deprived microglia by targeting toll-like receptor 4. J Neurochem. 2015;132:713–23. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25545945.

138.Mukaro VR, Quach A, Gahan ME, Boog B, Huang ZH, Gao X, et al. Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation. Nat Commun. 2018;9:1365. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29636466.

139.Dou G, Tian R, Liu X, Yuan P, Ye Q, Liu J, et al. Chimeric apoptotic bodies functionalized with natural membrane and modular delivery system for inflammation modulation. Sci Adv. 2020;6:eaba2987. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32832662.

140.Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol. 2016;17:611–25. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27461391.

141.Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15585754.

142.Weddell JC, Chen S, Imoukhuede PI. VEGFR1 promotes cell migration and proliferation through PLCgamma and PI3K pathways. NPJ Syst Biol Appl. 2018;4:1. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29263797.

143.Chang CH, Pauklin S. Extracellular vesicles in pancreatic cancer progression and therapies. Cell Death Dis. 2021;12:973. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34671031.

144.Chen K, Li Y, Xu L, Qian Y, Liu N, Zhou C, et al. Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment. Stem Cell Res Ther. 2022;13:238. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35672766.

145.Xia L, Fu GS, Yang JX, Zhang FR, Wang XX. Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension. Cytotherapy. 2009;11:492–502. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19526390.

146.Hansmann G, Chouvarine P, Diekmann F, Giera M, Ralser M, Mülleder M, et al. Human umbilical cord mesenchymal stem cell-derived treatment of severe pulmonary arterial hypertension. Nature Cardiovascular Research. 2022;1:568–76. https://doi.org/10.1038/s44161-022-00083-z.

147.Bian X, Ma K, Zhang C, Fu X. Therapeutic angiogenesis using stem cell-derived extracellular vesicles: an emerging approach for treatment of ischemic diseases. Stem Cell Res Ther. 2019;10:158. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31159859.

148.Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–30. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22992590.

149.Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–38. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27108839.

150.Patel NK, Nunez JH, Sorkin M, Marini S, Pagani CA, Strong AL, et al. Macrophage TGF-beta signaling is critical for wound healing with heterotopic ossification after trauma, JCI. Insight. 2022;7(20). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/36099022. https://doi.org/10.1172/jci.insight.144925.

151.Kiritsi D, Nystrom A. The role of TGFbeta in wound healing pathologies. Mech Ageing Dev. 2018;172:51–8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29132871.

152.Zhang L, Wei W, Ai X, Kilic E, Hermann DM, Venkataramani V, et al. Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-beta/Smad2/3 pathway. Cell Death Dis. 2021;12:1068. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34753919.

153.Brennan MA, Layrolle P, Mooney DJ. Biomaterials functionalized with MSC secreted extracellular vesicles and soluble factors for tissue regeneration. Adv Funct Mater. 2020;30(37). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/32952493. https://doi.org/10.1002/adfm.201909125.

154.Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer. 2017;17:38–53. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27932800.

155.Gomes LR, Terra LF, Wailemann RA, Labriola L, Sogayar MC. TGF-beta1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells. BMC Cancer. 2012;12:26. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22260435.

156.Lai P, Weng J, Guo L, Chen X, Du X. Novel insights into MSC-EVs therapy for immune diseases. Biomark Res. 2019;7:6. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/30923617.

157.Helissey C, Guitard N, Thery H, Goulinet S, Mauduit P, Girleanu M, et al. Two new potential therapeutic approaches in radiation cystitis derived from mesenchymal stem cells: extracellular vesicles and conditioned medium. Biology (Basel). 2022;11(7). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/36101361. https://doi.org/10.3390/biology11070980.

158.Jere SW, Abrahamse H, Houreld NN. The JAK/STAT signaling pathway and photobiomodulation in chronic wound healing. Cytokine Growth Factor Rev. 2017;38:73–9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29032938.

159.Lee JH, Lee CW, Park SH, Choe KM. Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during drosophila wound healing. J Cell Sci. 2017;130:1917–28. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28424232.

160.Harrison DA. The Jak/STAT pathway, Cold Spring Harb Perspect Biol. 2012;4(3). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/22383755. https://doi.org/10.1101/cshperspect.a011205.

161.Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6:402. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34824210.

162.Xie J, Wu X, Zheng S, Lin K, Su J. Aligned electrospun poly(L-lactide) nanofibers facilitate wound healing by inhibiting macrophage M1 polarization via the JAK-STAT and NF-kappaB pathways. J Nanobiotechnology. 2022;20:342. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35883095.

163.Li Y, Tan J, Miao Y, Zhang Q. MicroRNA in extracellular vesicles regulates inflammation through macrophages under hypoxia. Cell Death Discov. 2021;7:285. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34635652.

164.Tang D, Cao F, Yan C, Fang K, Ma J, Gao L, et al. Extracellular vesicle/macrophage Axis: potential targets for inflammatory disease intervention. Front Immunol. 2022;13:705472. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35769456.

165.Asati V, Mahapatra DK, Bharti SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives. Eur J Med Chem. 2016;109:314–41. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26807863.

166.Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18:189–218. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14737178.

167.Li HW, Zeng HS. Regulation of JAK/STAT signal pathway by miR-21 in the pathogenesis of juvenile idiopathic arthritis. World J Pediatr. 2020;16:502–13. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/31641939.

168.Narauskaite D, Vydmantaite G, Rusteikaite J, Sampath R, Rudaityte A, Stasyte G, et al. Extracellular vesicles in skin wound healing. Pharmaceuticals (Basel). 2021;14(8). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/34451909.

169.Hade MD, Suire CN, Mossell J, Suo Z. Extracellular vesicles: emerging frontiers in wound healing. Med Res Rev. 2022;42:2102–25. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35757979.

170.Hou Y, Li J, Guan S, Witte F. The therapeutic potential of MSC-EVs as a bioactive material for wound healing. Engineered Regeneration. 2021;2:182–94.

171.Cabral J, Ryan AE, Griffin MD, Ritter T. Extracellular vesicles as modulators of wound healing. Adv Drug Deliv Rev. 2018;129:394–406. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29408181.

172.Bailey AJM, Li H, Kirkham AM, Tieu A, Maganti HB, Shorr R, et al. , MSC-derived extracellular vesicles to heal diabetic wounds: a systematic review and meta-analysis of preclinical animal studies, Stem Cell Rev Rep, 2022, 18, 968–79. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33893619. https://doi.org/10.1007/s12015-021-10164-4.

173.Born LJ, Chang KH, Shoureshi P, Lay F, Bengali S, Hsu ATW, et al. HOTAIR-loaded mesenchymal stem/stromal cell extracellular vesicles enhance angiogenesis and wound healing. Adv Healthc Mater. 2022;11(5):e2002070. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33870645.

174.Dai W, Dong Y, Han T, Wang J, Gao B, Guo H, et al. Microenvironmental cue-regulated exosomes as therapeutic strategies for improving chronic wound healing. NPG Asia Materials. 2022;14(1). https://doi.org/10.1038/s41427-022-00419-y.

175.Vu NB, Nguyen HT, Palumbo R, Pellicano R, Fagoonee S, Pham PV. Stem cell-derived exosomes for wound healing: current status and promising directions. Minerva Med. 2021;112:384–400. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33263376.

176.Xie Y, Yu L, Cheng Z, Peng Y, Cao Z, Chen B, et al. SHED-derived exosomes promote LPS-induced wound healing with less itching by stimulating macrophage autophagy. J Nanobiotechnology. 2022;20:239. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35597946.

177.Yu Z, Hao R, Du J, Wu X, Chen X, Zhang Y, et al. A human cornea-on-a-chip for the study of epithelial wound healing by extracellular vesicles. iScience. 2022;25:104200. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35479406.

178.Prasai A, Jay JW, Jupiter D, Wolf SE, El Ayadi A, Role of exosomes in dermal wound healing: a systematic review, J Invest Dermatol, 2022, 142, 662–678 e668. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34461128. https://doi.org/10.1016/j.jid.2021.07.167.

179.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;47:3793–803. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31556314.

180.Rincon-Benavides MA, Mendonca NC, Cuellar-Gaviria TZ, Salazar-Puerta AI, Ortega-Pineda L, Blackstone BN, et al. Engineered Vasculogenic extracellular vesicles drive nonviral direct conversions of human dermal fibroblasts into induced endothelial cells and improve wound closure. Advanced Therapeutics. 2023;6:2200197. Retrieved from https://onlinelibrary.wiley.com/doi/abs/10.1002/adtp.202200197.

181.Lu S, Lu L, Liu Y, Li Z, Fang Y, Chen Z, et al. Native and engineered extracellular vesicles for wound healing, front Bioeng. Biotechnol. 2022;10:1053217. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/36568307.

182.Kim S, Shin Y, Choi Y, Lim K-M, Jeong Y, Dayem AA, et al. Improved wound healing and skin regeneration ability of 3,2′-Dihydroxyflavone-treated mesenchymal stem cell-derived extracellular vesicles. Int J Mol Sci. 2023;24(8). https://doi.org/10.3390/ijms24086964.

183.Chen J, Tan Q, Yang Z, Jin Y. Engineered extracellular vesicles: potentials in cancer combination therapy. J Nanobiotechnology. 2022;20:132. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35292030.

184.Jayasinghe MK, Pirisinu M, Yang Y, Peng B, Pham TT, Lee CY, et al. Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy. Theranostics. 2022;12:3288–315. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35547755.

185.White MJV, Briquez PS, White DAV, Hubbell JA. VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes. NPJ Regen Med. 2021;6:76. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34795305.

186.Wang Y, Zhao M, Liu S, Guo J, Lu Y, Cheng J, et al. Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases. Cell Death Dis. 2020;11:924. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33116121.

187.Totemeyer S, Sheppard M, Lloyd A, Roper D, Dowson C, Underhill D, et al. IFN-gamma enhances production of nitric oxide from macrophages via a mechanism that depends on nucleotide oligomerization domain-2. J Immunol. 2006;176:4804–10. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16585574.

188.Sahoo S, Kariya T, Ishikawa K. Targeted delivery of therapeutic agents to the heart. Nat Rev Cardiol. 2021;18:389–99. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33500578.

189.Murphy DE, de Jong OG, Brouwer M, Wood MJ, Lavieu G, Schiffelers RM, et al. Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking. Exp Mol Med. 2019;51:1–12. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30872574.

190.Pomatto MAC, Bussolati B, D'Antico S, Ghiotto S, Tetta C, Brizzi MF, et al. Improved loading of plasma-derived extracellular vesicles to encapsulate antitumor miRNAs. Mol Ther Methods Clin Dev. 2019;13:133–44. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30788382.

191.Han Y, Jones TW, Dutta S, Zhu Y, Wang X, Narayanan SP, et al. Overview and update on methods for cargo loading into extracellular vesicles. Processes (Basel). 2021;9(2). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/33954091.

192.Li T, Zhang L, Lu T, Zhu T, Feng C, Gao N, et al. Engineered extracellular vesicle-delivered CRISPR/CasRx as a novel RNA editing tool. Adv Sci (Weinh). 2023;10(10):e2206517. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/36727818.

193.Jang SC, Economides KD, Moniz RJ, Sia CL, Lewis N, McCoy C, et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun Biol. 2021;4:497. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33888863.

194.Martini PGV, Guey LT. A new era for rare genetic diseases: messenger RNA therapy. Hum Gene Ther. 2019;30:1180–9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31179759.

195.Lai J, Huang C, Guo Y, Rao L. Engineered extracellular vesicles and their mimics in cardiovascular diseases. J Control Release. 2022;347:27–43. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35508222.

196.Fan Z, Jiang C, Wang Y, Wang K, Marsh J, Zhang D, et al. Engineered extracellular vesicles as intelligent nanosystems for next-generation nanomedicine. Nanoscale Horiz. 2022;7:682–714. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35662310.

197.Estes S, Konstantinov K, Young JD. Manufactured extracellular vesicles as human therapeutics: challenges, advances, and opportunities. Curr Opin Biotechnol. 2022;77:102776. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/36041354.

198.Zhang X, Zhang H, Gu J, Zhang J, Shi H, Qian H, et al. Engineered extracellular vesicles for cancer therapy. Adv Mater. 2021;33:e2005709. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33644908.

199.Mentkowski KI, Snitzer JD, Rusnak S, Lang JK. Therapeutic potential of engineered extracellular vesicles. AAPS J. 2018;20:50. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29546642.

200.Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol. 2021;16:748–59. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34211166.

201.Zhang J, Ji C, Zhang H, Shi H, Mao F, Qian H, et al. Engineered neutrophil-derived exosome-like vesicles for targeted cancer therapy. Sci Adv. 2022;8:eabj8207. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35020437.

202.Mukherjee A, Bisht B, Dutta S, Paul MK. Current advances in the use of exosomes, liposomes, and bioengineered hybrid nanovesicles in cancer detection and therapy. Acta Pharmacol Sin. 2022;43:2759–76. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35379933.

203.Corso G, Mager I, Lee Y, Gorgens A, Bultema J, Giebel B, et al. Reproducible and scalable purification of extracellular vesicles using combined bind-elute and size exclusion chromatography. Sci Rep. 2017;7:11561. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28912498.

204.Watson DC, Johnson S, Santos A, Yin M, Bayik D, Lathia JD, et al. Scalable isolation and purification of extracellular vesicles from Escherichia coli and other bacteria. J Vis Exp. 2021;(176). Retrieved from; https://www.ncbi.nlm.nih.gov/pubmed/34723953.

205.Bellotti C, Lang K, Kuplennik N, Sosnik A, Steinfeld R. High-grade extracellular vesicles preparation by combined size-exclusion and affinity chromatography. Sci Rep. 2021;11:10550. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34006937.

206.Xu R, Simpson RJ, Greening DW. A protocol for isolation and proteomic characterization of distinct extracellular vesicle subtypes by sequential centrifugal ultrafiltration. Methods Mol Biol. 2017;1545:91–116. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27943209.

207.Zhang F, Guo J, Zhang Z, Duan M, Wang G, Qian Y, et al. Application of engineered extracellular vesicles for targeted tumor therapy. J Biomed Sci. 2022;29:14. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/35189894.

208.Man K, Brunet MY, Jones MC, Cox SC. Engineered extracellular vesicles: tailored-made nanomaterials for medical applications. Nanomaterials (Basel). 2020;10(9): Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32942556.

209.de Abreu RC, Fernandes H, da Costa Martins PA, Sahoo S, Emanueli C, Ferreira L. Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat Rev Cardiol. 2020;17:685–97. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32483304.

210.Lyu Y, Guo Y, Okeoma CM, Yan Z, Hu N, Li Z, et al. Engineered extracellular vesicles (EVs): promising diagnostic/therapeutic tools for pediatric high-grade glioma. Biomed Pharmacother. 2023;163:114630. Retrieved from https://www.sciencedirect.com/science/article/pii/S0753332223004183.

211.Zhuang J, Tan J, Wu C, Zhang J, Liu T, Fan C, et al. Extracellular vesicles engineered with valency-controlled DNA nanostructures deliver CRISPR/Cas9 system for gene therapy. Nucleic Acids Res. 2020;48:8870–82. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32810272.

212.Gualerzi A, Kooijmans SAA, Niada S, Picciolini S, Brini AT, Camussi G, et al. Raman spectroscopy as a quick tool to assess purity of extracellular vesicle preparations and predict their functionality. J Extracell Vesicles. 2019;8:1568780. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30728924.

213.Upadhya R, Madhu LN, Attaluri S, Gitai DLG, Pinson MR, Kodali M, et al. Extracellular vesicles from human iPSC-derived neural stem cells: miRNA and protein signatures, and anti-inflammatory and neurogenic properties. J Extracell Vesicles. 2020;9:1809064. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32944193.

214.Cai T, Zhang Q, Wu B, Wang J, Li N, Zhang T, et al. LncRNA-encoded microproteins: a new form of cargo in cell culture-derived and circulating extracellular vesicles. J Extracell Vesicles. 2021;10(9):e12123. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34276900.

215.Maugeri M, Nawaz M, Papadimitriou A, Angerfors A, Camponeschi A, Na M, et al. Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells. Nat Commun. 2019;10:4333. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31551417.

216.Liang, Y., Duan, L., Lu, J., & Xia, J., Engineering exosomes for targeted drug delivery, Theranostics, 2021, 11, 3183–95. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/33537081. https://doi.org/10.7150/thno.52570.

217.Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010;51:2105–20. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/20424270.

218.Cho K, Kook H, Kang S, Lee J. Study of immune-tolerized cell lines and extracellular vesicles inductive environment promoting continuous expression and secretion of HLA-G from semiallograft immune tolerance during pregnancy. J Extracell Vesicles. 2020;9:1795364. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/32944184.

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