Review
Copyright ©The Author(s) 2022.
World J Diabetes. Dec 15, 2022; 13(12): 1066-1095
Published online Dec 15, 2022. doi: 10.4239/wjd.v13.i12.1066
Table 1 Mesenchymal stem cell-derived exosomes application of diabetic full-thickness acute/chronic cutaneous wounds model
No.
Ref.
Institution(Nation)
Exosomes source
Intervention, administration, dose and time
Control
Model species
Wound diameter
Therapeutic effect
Molecular mechanism
1Yang et al[140], 2020The Third Affiliated Hospital of Southern Medical University(China)Human umbilical cord 1 HUCMSC-Exos + PF-127 hydrogel; injected topically; 100 µg in 100 µL PF-127 (24%); at Day 0PBS (100 µL)Rats (Sprague-Dawley)10 mm × 2 (1.5 cm apart)1 Accelerated wound closure rate
2 New hair follicle formation, fibroblasts proliferation, sufficient and order collagen deposition
2 HUCMSC-Exos + PF-127 hydrogel; injected topically; 100 µg in 100 µL PBS; at Day 0
3 Reduced inflammatory cell infiltration
4 Higher microvessel densities and higher number of blood vessels (CD31, MVD)
3 PF-127 hydrogel; injected topically; 100 µL PF-127 (24%); at Day 0
5 Promoted cell proliferation (Ki67) and enhanced regeneration of granulation tissue
6 Upregulated expression of VEGF and TGF-β
7 Hydrogel supported exosome survival and biological activity
2Wang et al[141], 2019The Affiliated Hospital of Wenzhou Medical University; Xi'an Jiaotong University(China)Mouse adipose tissue1 AMSC-Exos + F127/OHA-EPL hydrogel; covered the wound; 10 μg; at Day 0SalineMice (ICR)8 mm × 2 mm1 Accelerated wound closure rates
2 Promoted cell proliferation and abundant granulation tissue in early stage of healing; reduced proliferative activities during the late repair stage to prohibit tissue hyperplasia
2 AMSC-Exos; covered the wound; 10 μg; at Day 0
3 Abundant and well-organized collagen fibers, more collagen deposition (Col I, Col III)
3 F127/OHA-EPL hydrogel; covered the wound; 10 μg; at Day 0
4 Faster re-epithelization (cytokeratin) and epithelial cell differentiation
5 Promoted angiogenesis (α-SMA) and blood vessels formation
6 Complete skin regeneration: skin appendages and less scar tissue appeared
3Liu et al[121], 2020Second Military Medical University; Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University(China)Human bone marrow1 Melatonin-pretreated BMSC-Exos (MT-Exo); injected subcutaneously at least six sites per wound; dose not mentioned; at Day 0PBSRats (Sprague-Dawley)20 mm1 Accelerated diabetic wound healingPTEN/AKT signaling pathway
2 Anti-inflammatory effect on macrophages by promoting M2 and inhibiting M1 polarization
3 Enhanced re-epithelialization (increased neoepithelium length)
4 Improved angiogenesis (α-SMA, CD31, Microfli perfusion) and collagen synthesis (Col I and III)
5 Activated the PTEN/AKT signaling pathway
2 BMSC-Exos; injected subcutaneously at least six sites per wound; dose not mentioned; at Day 0
4Pomatto et al[104], 2021University of Turin(Italy)Human bone marrowBMSC-EVs + carboxymethylcellulose; applied on the wound; 1 × 109 in 25 µL of vehicle; at Day 0, 3, 7 and 10carboxymethylcellulose high viscosity 10 mg/mL (25 µL)Mice (NSG)6 mm × 8 mmNot effective and did not reduce the wound closure rate
Human adipose tissueAMSC-EVs + carboxymethylcellulose; applied on the wound; 1 × 109 in 25 µL of vehicle; at Day 0, 3, 7, 10 and 141 Accelerated cutaneous wound healing
2 Reduced size of the scar
3 Increased epithelial thickness and re-epithelization
4 Promoted angiogenesis (the number of vessels)
5Shi et al[139], 2020Affiliated Hospital of Nantong university(China)Human adipose tissue1 mmu_circ_0000250-modified AMSC-Exos;injected subcutaneously at four sites around the wound;200 μg in 100 μL PBS;at Day 0PBS (100 μL)Mice (C57BL)4 mm1 Accelerated cutaneous wound healingmmu_circ_0000250/miR-128-3p/SIRT1-mediated autophagy
2 Reduced scar areas
3 Enhanced angiogenesis (CD31, vessel density)
4 Suppressed apoptosis of skin tissue
5 Suppressed expression of miR-128-3p but promoted SIRT1 expression
2 AMSC-Exos; injected subcutaneously at four sites around the wound; 200 μg in 100 μL PBS; at Day 0
6 Increased expression of autophagy-related gene (LC3)
6Hu et al[138], 2021Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology(China)Rat bone marrow1 Pioglitazone-treated BMSC-Exos (PGZ-Exos); injected subcutaneously(at least six sites per wound); 100 μg in 100 μL PBS; at Day 0PBS (100 μL)Rats (Sprague-Dawley)15 mm1 Accelerated cutaneous wound healingPTEN/PI3K/AKT/eNOS pathway
2 Enhanced re-epithelization
3 Promoted collagen synthesis (Col I, Col III) and collagen deposition, indicating more superior ECM remodeling ability
4 Enhanced angiogenesis (VEGF, CD31) and blood flow of the wound
2 BMSC-Exos; injected subcutaneously (at least six sites per wound); 100 μg in 100 μL PBS; at Day 0
7Yu et al[137], 2020Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University; Second Military Medical University(China)Human bone marrow1 Atorvastatin-pretreated BMSC-Exos (ATV-Exos); injected subcutaneously (six points); dose not mentioned; at Day 0PBSRats (Sprague-Dawley)20 mm1 Accelerated cutaneous wound healingmiR-221-3p /PTEN/AKT/eNOS pathway
2 Increased re-epithelization (more epithelial structures and longer neuroepithelium)
2 BMSC-Exos; injected subcutaneously (six points); dose not mentioned; at Day 0
3 Promoted collagen synthesis and deposition, indicating more superior ECM remodeling ability (thicker wavy collagen fibers and more extensive collagen deposition arranged neatly)
4 Superior biosafety of the therapy of exosomes
5 Enhanced angiogenesis (CD31, α-SMA and Microfil perfusion)
8Zhao et al[123], 2021Tongji University(China)Human adipose tissue1. AMSC-Exos; smeared at the wound; 200 μg in 200 μL PBS; 3 times/day, 2 wkPBS;UntreatedMice (db/db)15 mm1 Accelerated cutaneous wound healing
2 Exosomes entered the dermis of wounds after smearing
2 Recombinant human epidermal growth factor (rhEGF); smeared at the wound;3 times/day, 2 wk
3 Mild hyperkeratosis and typical fibrous structures with new glands and hair follicles, implying enhanced tissue remodeling
3 AMSC-CM; smeared at the wound; 3 times/day, 2 wk
4 Enhanced collagen synthesis (Col I, Col III), deposition and remodeling (large amounts, large area, regular arrangement and dense distribution of new collagen)
5 Enhanced cell proliferation and inhibited apoptosis
6 Increased blood vessel intensity and promoted angiogenesis (CD31, VEGF)
7 Repaired skin barrier functions (elevated expression levels Filaggrin, Loricrin, and AQP3)
8 Suppressed expression of inflammatory cytokines (IL-6, TNF-α, CD14, CD19 and CD68)
9 Negatively regulated MMP1 and MMP3 expression in promoting collagen synthesis
9Tao et al[150], 2017Shanghai Jiao Tong University Affiliated Sixth People’s Hospital(China)Human synovial membrane1 miR-126-3p overexpressed SMSC-Exos + chitosan wound dressings; placed on the wound bed with pressure dressing; at Day 0UntreatedRats (Sprague-Dawley)18 mm1 Accelerated cutaneous wound healingPI3K/AKT and MAPK/ERK signaling pathways
2 Enhanced angiogenesis (microcomputed tomography, CD31, α-SMA)
3 Promoted re-epithelialization, granulation tissue formation, collagen alignment and deposition, implying enhanced ECM remodeling
2 Chitosan wound dressings; placed on the wound bed with pressure dressing; at Day 0
4 Accelerated development of hair follicles and sebaceous glands
10Ti et al[126], 2015Chinese PLA General Hospital(China)Human umbilical cord 1 LPS-pretreated HUCMSC-Exos; injected dispersively into the wound edge; 60 μg in 0.5 mL PBS; at Day 0UntreatedRats10 mm1 Accelerated cutaneous wound healinglet-7b/TLR4/NF-κB/STAT3/AKT pathway
2 Decreased inflammatory cell infiltration
3 Regulate macrophage polarization to M2 macrophages
2 HUCMSC-Exos; injected dispersively into the wound edge; 60 μg in 0.5 mL PBS; at Day 0
4 Promoted the appearance of new small capillaries
11Li et al[136], 2020The Fourth Affiliated Hospital of Harbin Medical University(China)Mouse bone marrow1 lncRNA H19 overexpressed BMSC-Exos; injected into the skin around the wound; at Day 0UntreatedMice (C57BL/6)10 mm1 Accelerated cutaneous wound healing.lncRNA H19/miR-152-3p/PTEN/ PI3K/AKT signaling pathway
2 Ameliorated inflammation of the wound (IL-10 ↑, IL-1β↓, TNF-α↓ and fewer inflammatory cells around the wound)
2 BMSC-Exos; injected into the skin around the wound; at Day 0
3 Promoted granulation tissue formation
4 Enhanced angiogenesis (Increased expression of VEGF, TGF-β1, α-SMA, and Col I)
5 Suppressed cell apoptosis
6 Interacted with miR-152-3p via PTEN-mediated PI3K/AKT signaling pathway (diminished miR-152-3p expression, elevated PTEN expression and decreased expression of PI3K, AKT and p-AKT)
12Shi et al.(2017)[142]Chinese PLA General Hospital(China)Human gingival tissue1 GMSC-Exos+ chitosan/silk hydrogel sponge; covered the wound with restraining bandage; 150 μg in 100 μl PBS; at Day 0, changed every 3 d1. PBS (100 μL);2. gauze (13 mm× 13 mm) covered the woundRats (Sprague-Dawley)10 mm1 Accelerated cutaneous wound healing
2 Promoted re-epithelialization, deposition and remodeling of ECM (more collagen deposition and thick wavy collagen fibers, the collagen fibers arranged in an orderly fashion similar to that of normal skin)
2 Chitosan/silk hydrogel sponge; covered the wound with restraining bandage; in 100 μL PBS; at Day 0, changed every 3 d
3 Enhanced angiogenesis (CD34, microvessel density)
4 Enhanced neuronal ingrowth (nerve fiber density)
13Xiao et al[151], 2021Nan Fang Hospital of Southern Medical University(China)Human adipose tissue1 AMSC-Exos + human acellular amniotic membrane (hAAM) scaffold; covered on the wound; 100 μg in 100 μL PBS; at Day 0, every other day, 3 times in totalPBS (100 μL)Mice (BALB/c)10 mm1 Accelerated cutaneous wound healing
2 Suppressed wound inflammatory responses (fewer inflammatory cells around the wound and higher recruitment of M2 macrophages to the wound sites)
2 AMSC-Exos; covered on the wound;100 μg in 100 μL PBS; at Day 0, every other day, 3 times in total
3 Enhanced angiogenesis (CD31)
4 Enhanced extracellular matrix (ECM) deposition (Col III)
5 Promoted re-epithelialization (completed epithelial and dermal regenerated)
3 hAAM patch; covered on the wound; at Day 0, every other day, 3 times in total
6 Failed regenerated hair follicle and sebaceous glands
14Yan et al[152], 2022Union Hospital, Tongji Medical College, Huazhong University of Science and Technology(China)Human umbilical cord 1 HUCMSC-Exos injected locally to the wound site; 100 μL, 50 μg/ml; at days 0, 3, 5, 7, 9, and 11PBS (100 μL)Mice (C57BL/6J)10 mm1 Accelerated cutaneous wound healing
2 Reduced oxidative stress (ROS)
3 Promoted granulation tissue formation
2 HUCMSC-Exos injected locally to the wound site; 100 μL, 100 μg/mL; at days 0, 3, 5, 7, 9, and 11
4 Enhanced angiogenesis (CD31, mean perfusion unit ratio)
15Geng et al[128], 2022Jinzhou Medical University(China)Rat bone marrow1 BMSC-Exos + carboxyethyl chitosan-dialdehyde carboxymethyl cellulose hydrogel; covered the wound; twice a day, two weeksUntreatedRats (Sprague-Dawley)20 mm1 Accelerated cutaneous wound healingVEGF-mediated PI3K/AKT signaling pathways
2 Promoted collagen deposition and remodeling, and fibrin regeneration
2 Carboxyethyl chitosan-dialdehyde carboxymethyl cellulose hydrogel; covered the wound; twice a day, two weeks3 Enhanced antibacterial effects by significantly inhibiting bacterial growth
4 Skew macrophage functional polarity from M1 (iNOS) towards an anti-inflammatory M2 phenotype (CD206)
5 Decreased inflammatory factors (IL-1β, TNF-α)
6 Promoted proliferation of blood vessels and angiogenesis (CD31)
16Gondaliya et al[153], 2022National Institute of Pharmaceutical Educationand Research(India)Bone marrow1 BMSC-Exos loaded with miR-155 inhibitor; injected subcutaneously; 0.1 μg/μL; 1 d after wound inductionUntreatedMice (C57BL/6)4 mm1 Accelerated cutaneous wound healing
2 Declined miR-155 levels with a concomitant increase in FGF-7
2 BMSC-Exos; injected subcutaneously; 0.1 μg/μL; 1 d after wound induction
3 Downregulated expression of MMP-2 and MMP-9
4 Declined expression of pro-inflammatory cytokines (TIMP-2, lymphotactin, sTNF RI, sTNF RII, and LIX); declined regulated upon activation, normal T cell expressed and secreted (RANTES) chemokine; downregulated pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and TGF-β1
3 BMSC-Exos loaded with negative control sequences; injected subcutaneously; 0.1 μg/μL; 1 d after wound induction
5 Promoted re-epithelialization, collagen synthesis and deposition, angiogenesis (α-SMA) and vascularization (CAM)
17Dalirfardouei et al[125], 2019Mashhad University of Medical Sciences(Iran)Human menstrual blood1 MenSC-Exos; injected intradermally; 10 μg in 100 μL of PBS; at Day 0PBS (100 μL)Mice (C57BL/6)8 mm1 Accelerated cutaneous wound healingNF-κB signaling pathway (possible)
2 Promoted re-epithelialization
2 MenSCs; injected intradermally; 1 × 106 cells in 100 μL of PBS; at Day 0
3 Induced macrophage polarization from M1 (iNOS) to M2 (Arg) phenotype
4 Enhanced angiogenesis (VEGF, microvessel density)
5 Improved collagen deposition (upregulated Col I/Col III ratio at Day 7, downregulated at Day 14)
6 Decreased size of scar tissues
7 Decreased cellularity in the granulation tissue
8 Decreased Rela gene expression at Day 4, enhanced at Day 7.
18Wang et al[124], 2022Affiliated Hospital of Nantong University(China)Rat bone marrow1 BMSC-Exos + 50 mg/kg intraperitoneal tertbutylhydroquinone (tBHQ); injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7PBSRats (Sprague-Dawley)15 mm1 Accelerated cutaneous wound healing
2 Promoted re-epithelialization and collagen deposition
3 Enhanced angiogenesis (CD31)
4 Reduced inflammation (decreased inflammatory cytokines TNF-α, IL-1β and increased anti-inflammatory cytokines IL-4, IL-10).
2 BMSC-Exos + 200 μL intravenous Lenti-sh-NC; injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7
3 BMSC-Exos; injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7
4 BMSC-Exos + 200 μL intravenous Lenti-sh-Nrf2; injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7
19Sun et al[127], 2022Nanjing Normal University; Nanjing University; Nanjing medical University; Nanjing Tech University(China)Human umbilical vein1 Engineering TNF-α/hypoxia-pretreated HUVMSC-Exos +PCOF; each subsequent day later, total 21 dPBSMice (C57BL/6)15 mm (S.aureus-infected chronic wounds)1 Accelerated cutaneous wound healingmiR-126/ SPRED1/RAS/ERK pathway (possible)
2 Reduced bacterial burden and suppressed bacterial colonization in the wound sites
2 Engineering TNF-α/hypoxia-pretreated HUVMSC-Exos; each subsequent day later, total 21 d
3 Reduced the inflammatory response (immune cells counting); decreased proinflammatory cytokines (TNF-α, IL-1β, IL-6); induced M2 (CD206) macrophages polarization
3 Vancomycin; each subsequent day later, total 21 d
4 PCOF; each subsequent day later, total 21 d
4 Promoted collagen deposition and remodeling, granulation formation, re-epithelialization and enhanced proliferation of fibroblasts
5 Enhanced cell proliferation (Ki67)
6 Suppressed oxidative stress induced by bacteria and peroxide substrates (reduced the content of oxidative biomarkers and (MDA) increased the antioxidant mediators (GSH-Px, SOD)
7 Promoted angiogenesis (upregulated miR-126, HIF-1α, VEGF, CD31 and α-SMA; increased neovascularization)
8 In vivo biosafety (blood system, heart, liver, kidney and other organs)
20Li et al[147], 2016Shanghai Normal University; Shanghai Jiao Tong University Affiliated Sixth People's Hospital(China)Human synovial tissue1 miR-126-3p overexpressed SMSC-Exos + hydroxyapatite/chitosan composite hydrogel; placed on the wound bed with pressure dressingUntreatedRats (Sprague-Dawley)18 mm1 Accelerated cutaneous wound healingActivated MAPK/ERK and PI3K/AKT pathways
2 Enhanced angiogenesis (μCT), formation and maturation of new vessels (CD31, α-SMA)
3 Promoted re-epithelialization, granulation tissue maturation, collagen alignment and deposition that indicated improved ECM remodeling
2 Hydroxyapatite/chitosan composite hydrogel; placed on the wound bed with pressure dressing
4 Accelerated growth of follicles and sebaceous glands
21Zhang et al[148], 2021Jinzhou Medical University(China)Human umbilical cord1 HUCMSC-Exos + polyvinyl alcohol (PVA)/alginate (Alg) nanohydrogel; locally transplanted; 300 μL; once a dayUntreatedRats (Sprague-Dawley)15 mm × 2 mm1 Accelerated cutaneous wound healingERK1/2 pathway
2 Enhanced re-epithelialization and hair follicles formation
3 Promoted collagen deposition and remodeling (increased and orderly arranged collagen fibers)
2 HUCMSC-Exos; locally transplanted; 300 μL; once a day
3 PVA/Alg nanohydrogel; locally transplanted; 300 μL; once a day
4 Promoted angiogenesis (CD31, α-SMA, SR-B1, VEGF)
22Han et al[154], 2022The First Affiliated Hospital of Zhengzhou University(China)Human bone marrow1 lncRNA KLF3-AS1 overexpressed BMSC-Exos; injected via tail vein; 100 µL; at Day 0UntreatedMice (BALB/c)Not mentioned1 Accelerated cutaneous wound healinglncRNA KLF3-AS1/miR-383/VEGFA signaling pathway
2 Minimized weight loss.
2 Negative control silenced BMSC-Exos;injected via tail vein;100 µL;at Day 03 Reduced inflammation (decreased IL-6 and IL-1β)
4 Promoted angiogenesis (CD31), collagen deposition and follicle regeneration
3 Negative control overexpressed BMSC-Exos; injected via tail vein; 100 µL; at Day 0
5 Decreased expression of miR-383 and increased VEGFA
4 lncRNA KLF3-AS1 silenced BMSC-Exos; injected via tail vein; 100 µL; at Day 0
23Ding et al[155], 2019Shanghai Jiao Tong University Affiliated Sixth People's Hospital(China)Human bone marrow1 Deferoxamine-preconditioned BMSC-Exos (DFO-Exos); injected subcutaneously around the wounds at four sites; 100 μg in 100 μL PBS; at Day 0PBS (100 μL)Rats (Sprague-Dawley)20 mm × 2 mm1 Accelerated cutaneous wound healingmiR-126/PTEN/PI3K/AKT pathway
2 Enhanced re-epithelialization and lower scar formation
3 Promoted collagen deposition (increased wavy collagen fibers)
2 BMSC-Exos; injected subcutaneously around the wounds at four sites; 100μg in 100μL PBS; at Day 0
4 Promoted angiogenesis (vessel density by micro-CT, CD31, α-SMA)
24Bian et al[135], 2020Chinese PLA General Hospital(China)Human deciduadMSC-sEVs; injected around the wounds at 4 sites (25 μL per site); 100 μL, 5.22 × 1011 particles/mL; at Day 7, 14, 21and 28PBS (100 μL)Mice (BKS-db)16 mm1 Accelerated cutaneous wound healingRAGE/RAS; Smad pathways
2 Reduced scar width
3 Accelerated collagen deposition (larger and better-organized collagen deposition)
4 Enhanced fibroblast proliferation (PCNA), migration (CXCR4), and differentiation abilities of fibroblast
5 Promoted angiogenesis (α-SMA)
6 Improved fibroblast senescent state (p21)
25Zhang et al[156], 2022Xijing Hospital of Fourth Military Medical University(China)Human adipose tissueAMSC-Exos; injected subcutaneously; 200 μg; 3 d after wound induction, for three consecutive daysPBS (100 μL)Mice (db/db)10 mm1 Accelerated cutaneous wound healingSIRT3/SOD2 pathway
2 Enhanced re-epithelialization
3 Promoted angiogenesis (CD34, VEGF)
4 Improved oxidative stress (MDA, T-AOC, SOD)
5 Reduced inflammatory cytokines (IL-1β, IL-6, TNF-α, MCP-1)
26Born et al[157], 2021University of Maryland; Johns Hopkins University School of Medicine(USA)Human bone marrow1 HOX transcript antisense RNA (HOTAIR) overexpressed BMSC-EVs; injected around the wound in a cross pattern of four sites; 50 μg in 50 μL PBS; at Day 3, four timesPBS (50 μL)Mice (db/db)8 mm1 Accelerated cutaneous wound healing
2 Promoted angiogenesis (CD31, VEGFA)
2 BMSC-EVs; injected around the wound in a cross pattern of four sites; 50 μg in 50 μL PBS; at Day 3, four times
27Teng et al[158], 2022Jiangnan University (China)Human umbilical cordHUCMSC-Exos; injected subcutaneously around the wounds at four sites; 100 μL (100 μg/mL); at Day 0PBS (100 μL)Rats (Sprague-Dawley)10 mm1 Accelerated cutaneous wound healing
2 Inhibited chronic inflammation: (decreased number of inflammatory cells); inhibited pro-inflammatory cytokines (TNF-α); induced M2 (CD206) macrophages polarization
3 Enhanced re-epithelialization
4 Promoted angiogenesis (increased new blood vessels, CD31, VEGF)
5 Promoted collagen synthesis and skin regeneration