Mesenchymal Stem Cell–derived Extracellular Vesicles: An Emerging Therapeutic Strategy for Diabetic Wound Healing

Anna Meiliana, Nurrani Mustika Dewi, Andi Wijaya

Abstract


One of the most serious side effects of diabetes is diabetic foot ulceration (DFU). It is a severe and extremely morbid illness that has been linked to higher mortality on its own. The development of effective wound therapeutics in the future may be influenced by our current and developing understanding of wound pathophysiology. By reestablishing cellular functioning, small extracellular vesicles (sEVs), a crucial medium for intercellular communications, exhibit encouraging therapeutic potential in the treatment of DFU. Mesenchymal stem cell (MSC) derived exosomes and engineered extracellular vesicles (EVs) have the potential to aid in the healing of wounds. Along with encouraging the growth and stimulation of endothelial cells, keratinocytes, and fibroblasts, they also have immunomodulatory and anti-inflammatory properties. They help prevent damaged cells from dying, revitalize senescent cells, and boost angiogenesis. MSC-EVs can be a safe, effective and ethical therapy for DFU by increasing M2 macrophages polarization, improving the proliferation, reducing scar, and improving angiogenesis.

KEYWORDS: mesenchymal stem cell, extracellular vesicle, diabetic wound, wound healing


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Järbrink K, Ni G, Sönnergren H, Schmidtchen A, Pang C, Bajpai R, et al. The humanistic and economic burden of chronic wounds: a protocol for a systematic re-view. Syst Rev. 2017; 6: 15. doi: 10.1186/S13643-016-0400-8, CrossRef.

Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022; 183: 109119, CrossRef.

Chang M, Nguyen TT. Strategy for treatment of infected diabetic foot ulcers. Acc Chem Res. 2021; 54(5): 1080-93, CrossRef.

Portou MJ, Yu R, Baker D, Xu S, Abraham D, Tsui J. Hyperglycaemia and ischaemia im-pair wound healing via toll-like receptor 4 pathway activation in vitro and in an experi-mental murine model. Eur J Vasc Endovasc Surg. 2020; 59(1): 117-27, CrossRef.

Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017; 376(24): 2367-75, CrossRef.

Athena A, Susanti I, Auron A, Atfat Malic R, Burhan A, Kumar V. The prevalence of am-putation in Regional Asia due to diabetic foot ulcers 2024: A systematic review and me-ta-analysis. Java Nursing Journal. 2024; 2(3): 220-34, CrossRef.

Lavery LA, Hunt NA, Ndip A, Lavery DC, Van Houtum W, Boulton AJM. Impact of chron-ic kidney disease on survival after amputation in individuals with diabetes. Diabetes Care. 2010; 33(11): 2365-69, CrossRef.

Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula W V, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are com-parable to cancer. J Foot Ankle Res. 2020; 13(1): 16, CrossRef.

Iversen MM, Tell GS, Riise T, Hanestad BR, Østbye T, Graue M, et al. History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trøndelag Health Study, Norway. Diabetes Care. 2009; 32(12): 2193-9, CrossRef.

Boyko EJ, Ahroni JH, Smith DG, Davignon D. Increased mortality associated with dia-betic foot ulcer. Diabet Med. 1996; 13(11): 967-72, CrossRef.

Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with foot ulcers. J Intern Med. 1993; 233(6): 485-91, CrossRef.

Martins-Mendes D, Monteiro-Soares M, Boyko EJ, Ribeiro M, Barata P, Lima J, et al. The independent contribution of diabetic foot ulcer on lower extremity amputa-tion and mortality risk. J Diabetes Complications. 2014; 28(5): 632-8, CrossRef.

Polikandrioti M, Vasilopoulos G, Koutelekos I, Panoutsopoulos G, Gerogianni G, Ba-batsikou F, et al. Quality of life in diabetic foot ulcer: Associated factors and the impact of anxiety/depression and adherence to self-care. Int J Low Extrem Wounds. 2020; 19(2): 165-79, CrossRef.

Zhou W, Duan Z, Zhao J, Fu R, Zhu C, Fan D. Glucose and MMP-9 dual-responsive hy-drogel with temperature sensitive self-adaptive shape and controlled drug release ac-celerates diabetic wound healing. Bioact Mater. 2022; 17: 1-17, CrossRef.

Martin P, Nunan R. Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol. 2015; 173(2): 370-8, CrossRef.

Louiselle AE, Niemiec SM, Zgheib C, Liechty KW. Macrophage polarization and diabet-ic wound healing. Transl Res. 2021; 236: 109-16, CrossRef.

Liu X, Wei Q, Sun Z, Cui S, Wan X, Chu Z, et al. Small extracellular vesicles: Yields, functionalization and applications in diabetic wound management. Interdisci-plinary Medicine. 2023; 1(4): e20230019, CrossRef.

Nourian Dehkordi A, Mirahmadi Babaheydari F, Chehelgerdi M, Raeisi Dehkordi S. Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies. Stem Cell Res Ther. 2019; 10(1): 111, CrossRef.

Pavathuparambil Abdul Manaph N, Al-Hawaas M, Bobrovskaya L, Coates PT, Zhou XF. Urine-derived cells for human cell therapy. Stem Cell Res Ther. 2018; 9(1): 189, CrossRef.

Andrzejewska A, Lukomska B, Janowski M. Mesenchymal stem cells: From roots to boost. Stem Cells. 2019; 37(7): 855-64, CrossRef.

Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE, Doevendans PA, et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 2007; 1(2): 129-37, CrossRef.

Liang X, Ding Y, Zhang Y, Tse HF, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: Current status and perspectives. Cell Transplant. 2014; 23(9): 1045-59,

https://doi.org/10.3727/096368913X667709">CrossRef.

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(3): 384-400, CrossRef.

Zipkin M. Exosome redux. Nat Biotechnol. Nat Biotechnol. 2019; 37(12): 1395-400, CrossRef.

Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, et al. Exosomes and their therapeutic potentials of stem cells. Stem Cells Int. 2016: 2016: 7653489, CrossRef.

Ryan Cross. Exosomes, nature's drug delivery fleet. C&EN Global Enterprise. 2018; 96: 22-4, CrossRef.

Lou G, Chen Z, Zheng M, Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. 2017; 49(6): e346, CrossRef.

Zeng QL, Liu DW. Mesenchymal stem cell-derived exosomes: An emerging therapeutic strategy for normal and chronic wound healing. World J Clin Cases. 2021; 9(22): 6218-33, CrossRef.

Wang PH, Huang BS, Horng HC, Yeh CC, Chen YJ. Wound healing. J Chin Med Assoc. 2018; 81(2): 94-101, CrossRef.

Wilkinson HN, Hardman MJ. Wound healing: Cellular mechanisms and pathological outcomes. Open Biol. 2020; 10(9): 200223, CrossRef.

Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci. 2016; 73(20): 3861-85, CrossRef.

Sharifi S, Hajipour MJ, Gould L, Mahmoudi M. Nanomedicine in healing chronic wounds: Opportunities and challenges. Mol Pharm. 2021; 18(2): 550-75, CrossRef.

Veith AP, Henderson K, Spencer A, Sligar AD, Baker AB. Therapeutic strategies for en-hancing angiogenesis in wound healing. Adv Drug Deliv Rev. 2019; 146: 97-125, CrossRef.

Nethi SK, Das S, Patra CR, Mukherjee S. Recent advances in inorganic nanomaterials for wound-healing applications. Biomater Sci. 2019; 7(7): 2652-74, CrossRef.

Doğruel H, Aydemir M, Balci MK. Management of diabetic foot ulcers and the challeng-ing points: An endocrine view. World J Diabetes. 2022; 13(1): 27-36, CrossRef.

Nowak NC, Menichella DM, Miller R, Paller AS. Cutaneous innervation in impaired di-abetic wound healing. Transl Res. 2021; 236: 87-108, CrossRef.

Stojadinovic O, Yin N, Lehmann J, et al. Increased number of Langerhans cells in the epidermis of diabetic foot ulcers correlates with healing outcome. Immunol Res. 2013; 57(1-3): 222-8, CrossRef.

Kruse CR, Nuutila K, Lee CCY, Kiwanuka E, Singh M, Caterson EJ, et al. The ex-ternal microenvironment of healing skin wounds. Wound Repair Regen. 2015; 23(4): 456-64, CrossRef.

Huang F, Lu X, Yang Y, Yang Y, Li Y, Kuai L, et al. Microenvironment-based diabet-ic foot ulcer nanomedicine. Adv Sci. 2023; 10(2): e2203308, CrossRef.

Tang WH, Martin KA, Hwa J. Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol. 2012: 3: 87, CrossRef.

Zhang W, Chen L, Xiong Y, Panayi AC, Abududilibaier A, Hu Y, et al. Antioxidant therapy and antioxidant-related bionanomaterials in diabetic wound healing. Front Bi-oeng Biotechnol. 2021: 9: 707479, CrossRef.

Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Bio-med Pharmacother. 2019: 112: 108615, CrossRef.

Baltzis D, Eleftheriadou I, Veves A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther. 2014; 31(8): 817-36, CrossRef.

Kruse CR, Singh M, Sørensen JA, Eriksson E, Nuutila K. The effect of local hyperglyce-mia on skin cells in vitro and on wound healing in euglycemic rats. J Surg Res. 2016; 206(2): 418-26, CrossRef.

Louiselle AE, Niemiec SM, Zgheib C, Liechty KW. Macrophage polarization and diabet-ic wound healing. Transl Res. 2021; 236: 109-16, CrossRef.

Zhao H, Huang J, Li Y, Lv X, Zhou H, Wang H, et al. ROS-scavenging hydrogel to promote healing of bacteria infected diabetic wounds. Biomaterials. 2020: 258: 120286, CrossRef.

Liu B, Yao X, Zhang Z, Li C, Zhang J, Wang P, et al. Synthesis of Cu2O nanostruc-tures with tunable crystal facets for electrochemical CO2 reduction to alcohols. ACS Appl Mater Interfaces. 2021; 13(33): 39165-77, CrossRef.

Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P. Autophagy: For better or for worse. Cell Res. 2012; 22(1): 43-61, CrossRef.

Xie Z, Klionsky DJ. Autophagosome formation: Core machinery and adaptations. Nat Cell Biol. 2007; 9(10): 1102-9, CrossRef.

Feng Y, He D, Yao Z, Klionsky DJ. The machinery of macroautophagy. Cell Res. 2014; 24(1): 24-41, CrossRef.

Catrina SB, Zheng X. Disturbed hypoxic responses as a pathogenic mechanism of dia-betic foot ulcers. Diabetes Metab Res Rev. 2016; 32 (Suppl 1): 179-85, CrossRef.

Desmet CM, Préat V, Gallez B. Nanomedicines and gene therapy for the delivery of growth factors to improve perfusion and oxygenation in wound healing. Adv Drug Deliv Rev. 2018; 129: 262-84, CrossRef.

Xiao H, Gu Z, Wang G, Zhao T. The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain thera-pies. Int J Med Sci. 2013; 10(10): 1412-21, CrossRef.

Zhu Y, Wang Y, Jia Y, Xu J, Chai Y. Roxadustat promotes angiogenesis through HIF-1α/VEGF/VEGFR2 signaling and accelerates cutaneous wound healing in diabetic rats. Wound Repair Regen. 2019; 27(4): 324-34, CrossRef.

Das S, Baker AB. Biomaterials and nanotherapeutics for enhancing skin wound heal-ing. Front Bioeng Biotechnol. 2016; 4: 82, CrossRef.

Lobmann R, Schultz G, Lehnert H. Proteases and the diabetic foot syndrome: Mecha-nisms and therapeutic implications. Diabetes Care. 2005; 28(2): 461-71, CrossRef.

Gethin G, O'Connor GM, Abedin J, Newell J, Flynn L, Watterson D, et al. Monitor-ing of pH and temperature of neuropathic diabetic and nondiabetic foot ulcers for 12 weeks: An observational study. Wound Repair Regen. 2018; 26(2): 251-6, CrossRef.

Worsley AL, Lui DH, Ntow-Boahene W, Song W, Good L, Tsui J. The importance of in-flammation control for the treatment of chronic diabetic wounds. Int Wound J. 2023; 20(6): 2346-59, CrossRef.

Theocharidis G, Thomas BE, Sarkar D, Mumme HL, Pilcher WJR, Dwivedi B, et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat Commun. 2022; 13(1): 181, CrossRef.

Shen TNY, Kanazawa S, Kado M, Okada K, Luo L, Hayashi A, et al. Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice. PLoS One. 2017; 12(5): e0178232, CrossRef.

Bannon P, Wood S, Restivo T, Campbell L, Hardman MJ, Mace KA. Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice. Dis Model Mech. 2013; 6(6): 1434-47, CrossRef.

Torbica T, Wicks K, Umehara T, Gungordu L, Alrdahe S, Wemyss K, et al. Chronic inflammation in response to injury: Retention of myeloid cells in injured tissue is driven by myeloid cell intrinsic factors. J Invest Dermatol. 2019; 139(7): 1583-92, CrossRef.

Davies LC, Taylor PR. Tissue-resident macrophages: then and now. Immunology. 2015; 144(4): 541-8, CrossRef.

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin In-vest. 2012; 122(3): 787-95, CrossRef.

Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018; 9: 419, CrossRef.

den Dekker AD, Davis FM, Joshi AD, Wolf SJ, Allen R, Lipinski J, et al. TNF-α reg-ulates diabetic macrophage function through the histone acetyltransferase MOF. JCI Insight. JCI Insight. 2020; 5(5): e132306, CrossRef.

Goren I, Müller E, Schiefelbein D, Christen U, Pfeilschifter J, Mühl H, et al. Sys-temic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages. J Invest Dermatol. 2007; 127(9): 2259-67, CrossRef.

Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, et al. Macrophage dys-function impairs resolution of inflammation in the wounds of diabetic mice. PLoS One. 2010; 5(3): e9539, CrossRef.

Kim J, Hematti P. Mesenchymal stem cell-educated macrophages: A novel type of al-ternatively activated macrophages. Exp Hematol. 2009; 37(12): 1445-53, CrossRef.

Chen L, Tredget EE, Wu PYG, Wu Y, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008; 3(4): e1886, CrossRef.

Jiang D, de Vries J, Muschhammer J, Sindrilaru A, Scharffetter-Kochanek K. Mouse model of immune complex-mediated vasculitis in dorsal skin and assessment of the neutrophil-mediated tissue damage. Bio Protoc. 2017; 7(24): e2660, CrossRef.

Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci. 2020; 21(19): 7038, CrossRef.

Zhang QZ, Su WR, Shi SH, Wilder-Smith P, Xiang AP, Wong A, et al. Human gin-giva-derived mesenchymal stem cells elicit polarization of m2 macrophages and en-hance cutaneous wound healing. Stem Cells. 2010; 28(10): 1856-68, CrossRef.

Uchiyama A, Motegi SI, Sekiguchi A, Fujiwara C, Perera B, Ogino S, et al. Mes-enchymal stem cells-derived MFG-E8 accelerates diabetic cutaneous wound healing. J Dermatol Sci. 2017; 86(3): 187-197, CrossRef.

Qi Y, Jiang D, Sindrilaru A, Stegemann A, Schatz S, Treiber N, et al. TSG-6 re-leased from intradermally injected mesenchymal stem cells accelerates wound heal-ing and reduces tissue fibrosis in murine full-thickness skin wounds. J Invest Dermatol. 2014; 134(2): 526-37, CrossRef.

Barminko JA, Nativ NI, Schloss R, Yarmush ML. Fractional factorial design to investi-gate stromal cell regulation of macrophage plasticity. Biotechnol Bioeng. 2014; 111(11): 2239-51, CrossRef.

Zhou L, Liu Z, Chen S, Qiu J, Li Q, Wang S, et al. Transcription factor EB mediat-ed autophagy promotes dermal fibroblast differentiation and collagen production by regulating endoplasmic reticulum stress and autophagy dependent secretion. Int J Mol Med. 2021; 47(2): 547-60, CrossRef.

Yoon JY, Park CG, Park BS, Kim EJ, Byeon GJ, Yoon JU. Effects of remifentanil precondi-tioning attenuating oxidative stress in human dermal fibroblast. Tissue Eng Regen Med. 2017; 14(2): 133-41, CrossRef.

Migneault F, Hébert MJ. Autophagy, tissue repair, and fibrosis: Adelicate balance. Ma-trix Biol. 2021; 100-101: 182-196, CrossRef.

Asai E, Yamamoto M, Ueda K, Waguri S. Spatiotemporal alterations of autophagy marker LC3 in rat skin fibroblasts during wound healing process. Fukushima J Med Sci. 2018; 64(1): 15-22, CrossRef.

Vescarelli E, Pilloni A, Dominici F, Pontecorvi P, Angeloni A, Polimeni A, et al. Autophagy activation is required for myofibroblast differentiation during healing of oral mucosa. J Clin Periodontol. 2017; 44(10): 1039-50, CrossRef.

Li L, Zhang J, Zhang Q, Zhang D, Xiang F, Jia J, et al. High glucose suppresses keratinocyte migration through the inhibition of p38 MAPK/autophagy pathway. Front Physiol. 2019; 10: 24, CrossRef.

Shaikh-Kader A, Houreld NN, Rajendran NK, Abrahamse H. The link between ad-vanced glycation end products and apoptosis in delayed wound healing. Cell Biochem Funct. 2019; 37(6): 432-42, CrossRef.

Guo Y, Lin C, Xu P, Wu S, Fu X, Xia W, et al. AGEs Induced autophagy impairs cu-taneous wound healing via stimulating macrophage polarization to M1 in diabetes. Sci Rep. 2016; 6: 36416, CrossRef.

Jin H, Zhang Z, Wang C, Tang Q, Wang J, Bai X, et al. Melatonin protects endo-thelial progenitor cells against AGE-induced apoptosis via autophagy flux stimulation and promotes wound healing in diabetic mice. Exp Mol Med. 2018; 50(11): 1-15, CrossRef.

Laughlin T, Tan Y, Jarrold B, Chen J, Li L, Fang B, et al. Autophagy activators stimulate the removal of advanced glycation end products in human keratinocytes. J Eur Acad Dermatol Venereol. 2020; 34 (Suppl 3): 12-8, CrossRef.

Aragonès G, Dasuri K, Olukorede O, Francisco SG, Renneburg C, Kumsta C, et al. Autophagic receptor p62 protects against glycation-derived toxicity and en-hances viability. Aging Cell. 2020; 19(11): e13257, CrossRef.

Ceccariglia S, Cargnoni A, Silini AR, Parolini O. Autophagy: A potential key contributor to the therapeutic action of mesenchymal stem cells. Autophagy. 2020; 16(1): 28-37, CrossRef.

Liu Y, Wang N, Zhang S, Liang Q. Autophagy protects bone marrow mesenchymal stem cells from palmitate induced apoptosis through the ROS JNK/p38 MAPK signaling pathways. Mol Med Rep. 2018; 18(2): 1485-94, CrossRef.

Lv B, Hua T, Li F, Han J, Fang J, Xu L, et al. Hypoxia-inducible factor 1 α protects mesenchymal stem cells against oxygen-glucose deprivation-induced injury via au-tophagy induction and PI3K/AKT/mTOR signaling pathway. Am J Transl Res. 2017; 9(5): 2492-9, PMID.

Zhang F, Gao F, Wang K, Liu X, Zhang Z. MiR-34a inhibitor protects mesenchymal stem cells from hyperglycaemic injury through the activation of the SIRT1/FoxO3a autophagy pathway. Stem Cell Res Ther. 2021; 12(1): 115, CrossRef.

An Y, Liu WJ, Xue P, Ma Y, Zhang LQ, Zhu B, et al. Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secre-tion. Cell Death Dis. 2018; 9(2): 58, CrossRef.

Ren H, Zhao F, Zhang Q, Huang X, Wang Z. Autophagy and skin wound healing. Burns Trauma. 2022: 10: tkac003, CrossRef.

Stoica AE, Grumezescu AM, Hermenean AO, Andronescu E, Vasile BS. Scar-free heal-ing: Current concepts and future perspectives. Nanomaterials. 2020; 10(11): 2179, CrossRef.

Malone M, Schultz G. Challenges in the diagnosis and management of wound infec-tion. Br J Dermatol. 2022; 187(2): 159-66, CrossRef.

Xiaojie W, Banda J, Qi H, Chang AK, Bwalya C, Chao L, et al. Scarless wound healing: Current insights from the perspectives of TGF-β, KGF-1, and KGF-2. Cytokine Growth Factor Rev. 2022; 66: 26-37, CrossRef.

Meng Z, Zhou D, Gao Y, Zeng M, Wang W. miRNA delivery for skin wound healing. Adv Drug Deliv Rev. 2018; 129: 308-18, CrossRef.

Evans J, Kaitu'u-Lino T, Salamonsen LA. Extracellular matrix dynamics in scar-free en-dometrial repair: perspectives from mouse in vivo and human in vitro studies. Biol Re-prod. 2011; 85(3): 511-23, CrossRef.

Moore AL, Marshall CD, Barnes LA, Murphy MP, Ransom RC, Longaker MT. Scarless wound healing: Transitioning from fetal research to regenerative healing. Wiley Inter-discip Rev Dev Biol. 2018; 7(2): 10.1002/wdev.309, CrossRef.

Guillamat-Prats R. The role of MSC in wound healing, scarring and regeneration. Cells. 2021; 10(7): 1729, CrossRef.

Yannas IV, Tzeranis DS. Mammals fail to regenerate organs when wound contraction drives scar formation. NPJ Regen Med. 2021; 6(1): 39, CrossRef.

Elsaie ML. Update on management of keloid and hypertrophic scars: A systemic re-view. J Cosmet Dermatol. 2021; 20(9): 2729-38, CrossRef.

Oliveira GV, Metsavaht LD, Kadunc BV, Jedwab SKK, Bressan MS, Stolf HO, et al. Treatment of keloids and hypertrophic scars. Position statement of the Brazilian expert group GREMCIQ. J Eur Acad Dermatol Venereol. 2021; 35(11): 2128-42, CrossRef.

Chen H, Hou K, Wu Y, Liu Z. Use of adipose stem cells against hypertrophic scarring or keloid. Front Cell Dev Biol. 2022; 9: 823694, CrossRef.

Deng CC, Zhang LX, Xu XY, Zhu DH, Cheng Q, Ma S, et al. Risk single-nucleotide polymorphism-mediated enhancer-promoter interaction drives keloids through long noncoding RNA down expressed in keloids. Br J Dermatol. 2023; 188(1): 84-93, CrossRef.

Zhou S, Xie M, Su J, Cai B, Li J, Zhang K. New insights into balancing wound healing and scarless skin repair. J Tissue Eng. 2023; 14: 20417314231185848, CrossRef.

Gunawardena TNA, Rahman MT, Abdullah BJJ, Abu Kasim NH. Conditioned media de-rived from mesenchymal stem cell cultures: The next generation for regenerative med-icine. J Tissue Eng Regen Med. 2019; 13(4): 569-86, CrossRef.

Crisostomo PR, Markel TA, Wang Y, Meldrum DR. Surgically relevant aspects of stem cell paracrine effects. Surgery. 2008; 143(5): 577-81, CrossRef.

Yang Z, Di Santo S, Kalka C. Current developments in the use of stem cell for therapeu-tic neovascularisation: Is the future therapy "cell-free"? Swiss Med Wkly. 2010; 140(4950): w13130, CrossRef.

Ratajczak MZ, Kucia M, Jadczyk T, Greco NJ, Wojakowski W, Tendera M, et al. Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: Can we translate stem cell-secreted paracrine factors and microvesicles into better thera-peutic strategies? Leukemia. 2012; 26(6): 1166-73, CrossRef.

Thieme S, Ryser M, Gentsch M, Navratiel K, Brenner S, Stiehler M, et al. Stromal cell-derived factor-1alpha-directed chemoattraction of transiently CXCR4-overexpressing bone marrow stromal cells into functionalized three-dimensional bio-mimetic scaffolds. Tissue Eng Part C Methods. 2009; 15(3): 687-96, CrossRef.

Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. Bio-med Res Int. 2014; 2014: 965849, CrossRef.

Chen L, Tredget EE, Wu PYG, Wu Y, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008; 3(4): 1886, CrossRef.

Andreas K, Sittinger M, Ringe J. Toward in situ tissue engineering: chemokine-guided stem cell recruitment. Trends Biotechnol. 2014; 32: 483-92, CrossRef.

Perin EC, Geng YJ, Willerson JT. Adult stem cell therapy in perspective. Circulation. 2003; 107(7): 935-38, CrossRef.

Makridakis M, Roubelakis MG, Vlahou A. Stem cells: Insights into the secretome. Bio-chim Biophys Acta Proteins Proteom. 2013; 1834: 2380-4, CrossRef.

Khosravi A, Cutler CM, Kelly MH, Chang R, Royal RE, Sherry RM, et al. Determi-nation of the elimination half-life of fibroblast growth factor-23. Journal of Clinical En-docrinology and Metabolism. 2007; 92(6): 2374-7, CrossRef.

Teixeira FG, Panchalingam KM, Assunção-Silva R, Serra SC, Mendes-Pinheiro B, Patrício P, et al. Modulation of the mesenchymal stem cell secretome using computer-controlled bioreactors: Impact on neuronal cell proliferation, survival and differentiation. Sci Rep. 2016; 6: 27791, CrossRef.

Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther. 2022; 7(1): 92, CrossRef.

Thurley K, Wu LF, Altschuler SJ. Modeling cell-to-cell communication networks using response-time distributions. Cell Syst. 2018; 6(3): 355-67.e5, CrossRef.

Shukla S, Currim F, Singh R. Do different exosome biogenesis pathways and selective cargo enrichment contribute to exosomal heterogeneity? Biol Cell. 2023; 115(7): e2200116, CrossRef.

Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: Masters of intercellular commu-nication and potential clinical interventions. J Clin Invest. 2016; 126(4): 1139-43, CrossRef.

Doyle L, Wang M. Overview of extracellular vesicles, their origin, composition, pur-pose, and methods for exosome isolation and analysis. Cells. 2019; 8(7): 727, CrossRef.

Zhang Q, Higginbotham JN, Jeppesen DK, Yang YP, Li W, McKinley ET, et al. Transfer of functional cargo in exomeres. Cell Rep. 2019; 27(3): 940-54.e6, CrossRef.

Lässer C, Jang SC, Lötvall J. Subpopulations of extracellular vesicles and their thera-peutic potential. Mol Aspects Med. 2018; 60: 1-14, CrossRef.

Negahdaripour M, Owji H, Eskandari S, Zamani M, Vakili B, Nezafat N. Small extracel-lular vesicles (sEVs): Discovery, functions, applications, detection methods and vari-ous engineered forms. Expert Opin Biol Ther. Expert Opin Biol Ther. 2021; 21(3): 371-94, CrossRef.

El Andaloussi S, Mäger I, Breakefield XO, Wood MJA. Extracellular vesicles: Biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013; 12(5): 347-57, CrossRef.

Varderidou-Minasian S, Lorenowicz MJ. Mesenchymal stromal/stem cell-derived ex-tracellular vesicles in tissue repair: Challenges and opportunities. Theranostics. 2020; 10(13): 5979-97, CrossRef.

Wolf P. The nature and significance of platelet products in human plasma. Br J Haema-tol. 1967; 13: 269-88, CrossRef.

Trams EG, Lauter CJ, Norman Salem J, Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta. 1981; 645(1): 63-70, CrossRef.

Raposo G, Nijman HW, Stoorvogel W, Leijendekker R, Harding CV, Melief CJM, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996; 183(3): 1161-72, CrossRef.

Kalra H, Drummen GPC, Mathivanan S. Focus on extracellular vesicles: Introducing the next small big thing. Int J Mol Sci. 2016; 17(2): 170, CrossRef.

Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014; 29: 116-25, CrossRef.

Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, Zhao K, et al. ExoCarta: A web-based compendium of exosomal cargo. J Mol Biol. 2016; 428(4): 688-92, CrossRef.

Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, et al. Vesiclepedia: A compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012; 10(12): e1001450, CrossRef.

Kim DK, Kang B, Kim OY, Choi DS, Lee J, Kim SR, et al. EVpedia: An integrated database of high-throughput data for systemic analyses of extracellular vesicles. J Ex-tracell Vesicles. 2013; 2, CrossRef.

Rashed MH, Bayraktar E, Helal GK, Abd-Ellah MF, Amero P, Chavez-Reyes A, et al. Exosomes: From garbage bins to promising therapeutic targets. Int J Mol Sci. 2017; 18(3): 538, CrossRef.

Mayor S, Pagano RE. Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol. 2007; 8(8): 603-12, CrossRef.

Charrin S, Le Naour F, Silvie O, Milhiet PE, Boucheix C, Rubinstein E. Lateral organiza-tion of membrane proteins: tetraspanins spin their web. Biochem J. 2009; 420(2): 133-54, CrossRef.

Lakkaraju A, Rodriguez-Boulan E. Itinerant exosomes: Emerging roles in cell and tissue polarity. Trends Cell Biol. 2008; 18(5): 199-209, CrossRef.

Gurunathan S, Kang MH, Jeyaraj M, Qasim M, Kim JH. Review of the isolation, charac-terization, biological function, and multifarious therapeutic approaches of exosomes. Cells. 2019; 8(4): 307, CrossRef.

Schorey JS, Bhatnagar S. Exosome function: From tumor immunology to pathogen bi-ology. Traffic. 2008; 9(6): 871-81, CrossRef.

Keshavarz M, Dianat-Moghadam H, Sofiani VH, Karimzadeh M, Zargar M, Moghoofei M, et al. miRNA-based strategy for modulation of influenza A virus infection. Epigenomics. 2018; 10(6): 829-44, CrossRef.

Li A, Zhang T, Zheng M, Liu Y, Chen Z. Exosomal proteins as potential markers of tumor diagnosis. J Hematol Oncol. 2017; 10(1): 175, CrossRef.

Rahmati S, Shojaei F, Shojaeian A, Rezakhani L, Dehkordi MB. An overview of current knowledge in biological functions and potential theragnostic applications of exo-somes. Chem Phys Lipids. 2020; 226: 104836, CrossRef.

Li X, Corbett AL, Taatizadeh E, Tasnim N, Little JP, Garnis C, et al. Challenges and opportunities in exosome research-Perspectives from biology, engineering, and cancer therapy. APL Bioeng. 2019; 3(1): 011503, CrossRef.

Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007; 25(10): 2648-59, CrossRef.

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

Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008; 180(4): 2581-7, CrossRef.

De Mayo T, Conget P, Becerra-Bayona S, Sossa CL, Galvis V, Arango-Rodríguez ML. The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice. PLoS One. 2017; 12(6): e0177533, CrossRef.

Kucharzewski M, Rojczyk E, Wilemska-Kucharzewska K, Wilk R, Hudecki J, Los MJ. Novel trends in application of stem cells in skin wound healing. Eur J Pharmacol. 2019; 843: 307-15, CrossRef.

Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev. 2015; 24(14): 1635-47, CrossRef.

Alonso-Goulart V, Ferreira LB, Duarte CA, Lima IL de, Ferreira ER, Oliveira BC de, et al. Mesenchymal stem cells from human adipose tissue and bone repair: A litera-ture review. Biotechnol Res Innov. 2018; 2: 74-80, CrossRef.

Yew TL, Hung YT, Li HY, Chen HW, Chen LL, Tsai KS, et al. Enhancement of wound healing by human multipotent stromal cell conditioned medium: The paracrine factors and p38 MAPK activation. Cell Transplant. 2011; 20(5): 693-706, CrossRef.

Walter MNM, Wright KT, Fuller HR, MacNeil S, Johnson WEB. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. Exp Cell Res. 2010; 316(7): 1271-81, CrossRef.

Yin K, Wang S, Zhao RC. Exosomes from mesenchymal stem/stromal cells: a new ther-apeutic paradigm. Biomark Res. 2019; 7: 1-8, CrossRef.

Zhang B, Yin Y, Lai RC, Tan SS, Choo ABH, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014; 23(11): 1233-44, CrossRef.

Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, et al. Exosome derived from human um-bilical cord mesenchymal stem cell mediates miR-181c attenuating burn-induced ex-cessive inflammation. EBioMedicine. 2016; 8: 72-82, CrossRef.

Wang J, Xia J, Huang R, Hu Y, Fan J, Shu Q, Xu J. Mesenchymal stem cell-derived extra-cellular vesicles alter disease outcomes via endorsement of macrophage polarization. Stem Cell Res Ther. 2020; 11: 424, CrossRef.

Xie M, Xiong W, She Z, Wen Z, Abdirahman AS, Wan W, Wen C. Immunoregulatory effects of stem cell-derived extracellular vesicles on immune cells. Front Immunol. 2020; 11: 13, CrossRef.

Kim H, Young Wang S, Kwak G, Yang Y, Chan Kwon I, Hwa Kim S, et al. Exosome-guided phenotypic Switch of M1 to M2 macrophages for cutaneous wound healing. Adv Sci. 2019; 6(20): 1900513, CrossRef.

Heo JS, Choi Y, Kim HO, Matta C. Adipose-derived mesenchymal stem cells promote M2 macrophage phenotype through exosomes. Stem Cells Int. 2019; 2019: 7921760, CrossRef.

Ren Z, Qi Y, Sun S, Tao Y, Shi R. Mesenchymal stem cell-derived exosomes: Hope for spinal cord injury repair. Stem Cells Dev. 2020; 29(23): 1467-78, CrossRef.

He X, Dong Z, Cao Y, Wang H, Liu S, Liao L, et al. MSC-derived exosome pro-motes M2 polarization and enhances cutaneous wound healing. Stem Cells Int. 2019; 2019: 7132708, CrossRef.

Luo Q, Guo D, Liu G, Chen G, Hang M, Jin M. Exosomes from MiR-126-overexpressing ADSCs are therapeutic in relieving acute myocardial ischaemic injury. Cell Physiol Bi-ochem. 2017; 44(6): 2105-16, CrossRef.

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

Zhang B, Wu X, Zhang X, Sun Y, Yan Y, Shi H, et al. Human umbilical cord mes-enchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem Cells Transl Med. 2015; 4(5): 513-22, CrossRef.

Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, et al. Endothelial progenitor cell-derived microvesicles activate an angiogenic pro-gram in endothelial cells by a horizontal transfer of mRNA. Blood. 2007; 110(7): 2440-8, CrossRef.

Bian X, Ma K, Zhang C, Fu X. Therapeutic angiogenesis using stem cell-derived extra-cellular vesicles: an emerging approach for treatment of ischemic diseases. Stem Cell Res Ther. 2019; 10: 158, CrossRef.

Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015; 13: 49, CrossRef.

Tutuianu R, Rosca AM, Iacomi DM, Simionescu M, Titorencu I. Human mesenchymal stromal cell-derived exosomes promote in vitro wound healing by modulating the bio-logical properties of skin keratinocytes and fibroblasts and stimulating angiogenesis. Int J Mol Sci. 2021; 22(12): 6239, CrossRef.

Hade MD, Suire CN, Mossell J, Suo Z. Extracellular vesicles: Emerging frontiers in wound healing. Med Res Rev. 2022; 42(6): 2102-25, CrossRef.

Zhang X, Yuan X, Shi H, et al. Exosomes in cancer: Small particle, big player. J Hematol Oncol. 2015; 8(1): 83, CrossRef.

Hu L, Wang J, Zhou X, Xiong Z, Zhao J, Yu R, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimiz-ing the characteristics of fibroblasts. Sci Rep. 2016; 6: 32993, CrossRef.

Wang L, Hu L, Zhou X, Xiong Z, Zhang C, Shehada HMA, et al. Exosomes secret-ed by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. Sci Rep. 2017; 7: 13321, CrossRef.

Duan M, Zhang Y, Zhang H, Meng Y, Qian M, Zhang G. Epidermal stem cell-derived ex-osomes promote skin regeneration by downregulating transforming growth factor-β1 in wound healing. Stem Cell Res Ther. 2020; 11(1): 452, CrossRef.

Qin X, He J, Wang X, Wang J, Yang R, Chen X. The functions and clinical application po-tential of exosomes derived from mesenchymal stem cells on wound repair: a review of recent research advances. Front Immunol. 2023; 14: 1256687, CrossRef.

Yang J, Chen Z, Pan D, Li H, Shen J. Umbilical cord-derived mesenchymal stem cell-derived exosomes combined pluronic F127 hydrogel promote chronic diabetic wound healing and complete skin regeneration. Int J Nanomedicine. 2020; 15: 5911-26, CrossRef.

Nooshabadi VT, Khanmohamadi M, Valipour E, Mahdipour S, Salati A, Malekshahi ZV, et al. Impact of exosome-loaded chitosan hydrogel in wound repair and layered dermal reconstitution in mice animal model. J Biomed Mater Res A. 2020; 108(11): 2138-49, CrossRef.

Shafei S, Khanmohammadi M, Heidari R, Ghanbari H, Taghdiri Nooshabadi V, Farzam-far S, et al. Exosome loaded alginate hydrogel promotes tissue regeneration in full-thickness skin wounds: An in vivo study. J Biomed Mater Res A. 2020; 108(3): 545-56, CrossRef.

Shi Q, Qian Z, Liu D, Sun J, Wang X, Liu H, et al. GMSC-derived exosomes com-bined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model. Front Physiol. 2017; 8: 904, CrossRef.

Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev. 2016; 106(Pt A): 148-56, CrossRef.

Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol. 2013; 200(4): 373-83, CrossRef.

Van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018; 19(4): 213-28, CrossRef.

Raiborg C, Stenmark H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature. 2009; 458(7237): 445-52, CrossRef.

Armstrong JP, Holme MN, Stevens MM. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano. 2017; 11(1): 69-83, CrossRef.

Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic be-havior. Cell. 2015; 161(5): 1046-57, CrossRef.

Ridder K, Sevko A, Heide J, Dams M, Rupp AK, Macas J, et al. Extracellular vesi-cle-mediated transfer of functional RNA in the tumor microenvironment. Oncoim-munology. 2015; 4(6): e1008371, CrossRef.

Mentkowski KI, Snitzer JD, Rusnak S, Lang JK. Therapeutic potential of engineered ex-tracellular vesicles. AAPS J. 2018; 20(3): 1-12, CrossRef.

Presolski SI, Hong VP, Finn MG. Copper-catalyzed azide-alkyne click chemistry for bio-conjugation. Curr Protoc Chem Biol. 2011; 3(4): 153-62, CrossRef.

Tian T, Zhang HX, He CP, Fan S, Zhu YL, Qi C, et al. Surface functionalized exo-somes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials. 2018: 150: 137-149, CrossRef.

Jia G, Han Y, An Y, Ding Y, He C, Wang X, et al. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials. 2018; 178: 302-16, CrossRef.

Kooijmans SAA, Fliervoet LAL, van der Meel R, Fens MHAM, Heijnen HFG, van Bergen En Henegouwen PMP, et al. PEGylated and targeted extracellular vesicles dis-play enhanced cell specificity and circulation time. J Control Release. 2016; 224: 77-85, CrossRef.

Huang L, Gu N, Zhang XE, Wang DB. Light-inducible exosome-based vehicle for en-dogenous RNA loading and delivery to leukemia cells. Adv Funct Mater. 2019; 29(9): 1807189, CrossRef.

Liu H, Zhang H, Han Y, Hu Y, Geng Z, Su J. Bacterial extracellular vesicles-based thera-peutic strategies for bone and soft tissue tumors therapy. Theranostics. 2022; 12(15): 6576-94, CrossRef.

Danilushkina AA, Emene CC, Barlev NA, Gomzikova MO. Strategies for engineering of extracellular vesicles. Int J Mol Sci. 2023; 24(17): 13247, CrossRef.

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, CrossRef.

Zhao H, Li Z, Wang Y, Zhou K, Li H, Bi S, et al. Bioengineered MSC-derived exo-somes in skin wound repair and regeneration. Front Cell Dev Biol. 2023: 11: 1029671, CrossRef.

Yang S, Chen S, Zhang C, Han J, Lin C, Zhao X, et al. Enhanced therapeutic effects of mesenchymal stem cell-derived extracellular vesicles within chitosan hy-drogel in the treatment of diabetic foot ulcers. J Mater Sci Mater Med. 2023; 34(9): 43, CrossRef.

Cassidy B, Kendrick C, Reeves ND, Pappachan JM, O'Shea C, Armstrong DG, et al. Diabetic foot ulcer grand challenge 2021: Evaluation and Summary. In: Yap MH, Cassidy B, Kendrick C, editors. Diabetic Foot Ulcers Grand Challenge - 2nd Challenge, DFUC 2021, Held in Conjunction with MICCAI 2021, Proceedings. 2021 Sep 27. Berlin: Springer Science and Business Media Deutschland GmbH; 2022. p.90-105, CrossRef.




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