Table 3.
Anti-inflammatory and immunomodulatory effects of MSC-exosomes.
| Category | Exosome Source | Nomenclature | Exosome Isolation | Related Exosomal Cargo | Secreted Factors or Expressed Genes Affected | Immunomodulatory Effects | Reference |
|---|---|---|---|---|---|---|---|
| Macrophage polarization | Human jaw bone marrow (JM-MSCs) Human BM-MSCs |
Exosomes | Ultracentrifugation ExoQuick (System Biosciences) |
miR-223 | TNF-α ↓ IL-10 ↑ |
Accelerated wound healing in mice Induced M2 macrophage polarization (CD206+ macrophage ↑) |
[85] |
| Human JM-MSCs Human BM-MSCs |
Exosomes | Ultracentrifugation | - | Collagen, Il-6, Ccl2, Cd206, Ccl7, Ccl17, Tnfα, Retnia ↓ Arg1 ↑ |
Reduced BPD through macrophage M22 polarization | [86] | |
| Human umbilical cord (UC)-MSCs | Exosomes | Ultracentrifugation | let-7b | TLR4, p-p65, iNOS ↓ p-STAT3, p-AKT, ARG1 ↑ |
Alleviated inflammation and enhanced diabetic cutaneous wound healing in rats Induced M2 macrophage polarization Inhibited TLR4 signaling pathway |
[87] | |
| Human UC-MSCs | Exosomes | PureExo (101Bio) |
miR-181c | TNF-α, IL-1β, TLR4, p65, p-p65 ↓ IL-10 ↑ |
Reduced burn-induced inflammation in rats Reduced neutrophil and macrophage infiltration (MPO+ cell, CD68+ cell ↓) Inhibited TLR4 signaling pathway |
[88] | |
| Human menstrual blood derived MSCs (MenSCs) | Exosomes | Ultracentrifugation | - | iNOS ↓ ARG1, VEGF ↑ |
Resolved inflammation and ameliorate cutaneous non-healing wounds in diabetic mice Induced M2 macrophage polarization |
[89] | |
| Mouse BM-MSCs | Exosomes | HPLC | let-7 | HMGA2, IGF2BP1 ↓ | Attenuated atherosclerosis in mice Reduced area of atherosclerotic plaques Promoted M2 macrophage polarization |
[90] | |
| Mouse BM-MSCs | Exosomes | Ultracentrifugation | miR-182 | IL-6, iNOS, IL-1 β, IL-6, TNF-α ↓ ARG1, IL-10, TGF-β ↑ |
Reduced myocardial ischemic-reperfusion injury in mice Reduced infarct size and inflammation Promoted M2 macrophage polarization |
[91] | |
| Human BM-MSCs | Exosomes | Ultracentrifugation | MT2A | IFN-γ, IL-1β, IL-6, TNF-α ↓ IL-10, Lyz1, Defa20, Defa29, Ang4 ↑ |
Reduced IBD by polarizing M2 macrophage in mice | [92] | |
| Rat ASCs | Exosomes | Ultracentrifugation | - | S1P, SphK1, S1PR1 ↑ AGR1, Ym1, TGF-β1, IL-10 ↑ IL-1β, IL-6, TNF-α, IFN-γ, p65 ↓ |
Reduced cardiac damage in rats Reduced fibrosis and apoptosis Promoted M2 macrophage polarization |
[93] | |
| Human ASCs | Exosomes | Exosome Isolation Kit (System Biosciences) |
- | CD163, ARG1, CD206, STAT6, MafB ↑ | Increased the expression of M2 macrophage markers | [94] | |
| Mouse ASCs | Exosomes | Ultrafiltration | STAT3 | ARG1, IL-10, tyrosine hydroxylase ↑ TNF-α, IL-12 ↓ |
Induced M2 macrophage polarization in obese mice ASC-exosome-educated M2 macrophage promoted WAT beiging |
[95] | |
| T cell regulation | Human BM-MSCs | Exosomes | ExoQuick (System Biosciences) |
- | TNF-α, IL-1β ↓ TGF-β ↑ |
Induced conversion of Th1 into Th2 Reduced differentiation of Th17 Increased the level of Tregs Induced apoptosis of PBMCs and CD3+ T cells |
[96] |
| Human BM-MSCs | Exosomes | Ultracentrifugation | - | IL-10, TGF-β ↑ | Promoted proliferation and immune-suppression capacity of Tregs | [97] | |
| Human UC-MSCs | Exosomes | PEG6000 precipitation | - | IL-10, IDO ↑ | Induced an increase of Tregs in PBMCs Inhibited proliferation of PBMCs |
[98] | |
| Human embryonic stem cell (ES)-MSCs | Exosomes | Tangential flow filtration + HPLC | EDA-FN | TNF-α, IL-1β, IL-6, IL-12p40 ↓ IL-10 ↑ |
Induced Tregs through activation of APCs in the MyD88-dependent manner Enhanced allogeneic skin graft |
[99] | |
| Mouse ASCs | Exosomes | Ultracentrifugation | - | IL-17, IFN-γ ↓ IL-4, IL-10, TGF-β ↑ |
Ameliorated autoimmune type 1 diabetes mellitus by increasing Tregs in mice | [100] | |
| Human BM-MSCs | Exosomes | Ultracentrifugation | - | IL-6, IL-12p70, IL-22, IL-17AF ↓ IDO ↑ |
Improved motor skill in the MS mouse experimental autoimmune encephalomyelitis model Increased Tregs and decreased infiltration and proliferation of pro-inflammatory T cells |
[101] | |
| Mouse BM-MSCs | Exosomes | Ultracentrifugation | - | IL-1, IL-2, IL-4, IL-10, TNF-α, IFN-γ ↓ | Decreased aminotransferase (ALT), liver necrotic areas, and apoptosis in Con A-induced liver injury in mice Increased Tregs |
[102] | |
| UC-MSCs | EVs | Size exclusion chromatography | - | - | Suppressed T cell proliferation | [105] | |
| B cell regulation | Human BM-MSCs | Exosomes | Ultracentrifugation | - | MZB1, CXCL8 ↑ IgM ↓ |
Reduced proliferation of T and B cells | [106] |
| Photoaging | Human BM-MSCs | Exosomes | Ultrafiltration | - | TNF-α, IL-1β ↓ TGF-β, CTLA4 ↑ |
Reduced photoaging of skin in mice Ameliorated inflammation |
[107] |
| Skin flap | Human ASCs | Exosomes | Ultracentrifugation | - | - | Enhanced neovascularization and survival of the skin flap in rats Reduced inflammation and apoptosis |
[108] |
| Atopic dermatitis (AD) | Human ASCs | Exosomes | Tangential flow filtration | - | IgE, IL-4, IL-5, IL-13, IL-17, IL-23, IL-31, IFN-γ, TNF-α, TSLP ↓ | Reduced pathological symptoms of AD in mice Reduced mast cell infiltration Reduced inflammatory dendritic epidermal cells (CD86+/CD206+ cells↓) |
[20,109] |
| Renal injury | Rat BM-MSCs | Exosomes | Ultracentrifugation | - | MDA, HIF1α, NOX2, Caspase 3, BAX, PARP1, MPO, ICAM1, IL-1β, NF-κB ↓ SOD, CAT, GPX, HO-1, BCL2, IL-10, bFGF, HGF, SOX9, VEGF ↑ |
Decreased histopathological score of kidney injury in rats Reduced the levels of blood urea nitrogen (BUN) and creatinine Reduced the level of oxidative stress Increased anti-oxidant status Reduced apoptosis and inflammation Improved regeneration and enhanced angiogenesis |
[110] |
| Mouse BM-MSCs | Exosomes | Ultracentrifugation | CCR2 | TNF-α, IL-6, IL-1β ↓ | Reduced BUN and creatinine in the mouse IR model Reduced infiltration of macrophages |
[111] | |
| Human UC-MSCs | Exosomes | Ultracentrifugation | - | PCNA, BCL-XL, BCL2, IL-1β, 4E-BP1 ↑ Bax, cytochrome C, Caspase-3, p65, TNF-α, IL-6, IL-1β, p-mTOR ↓- |
Reduced cisplatin-induced AKI in rats Reduced BUN and creatinine |
[112] | |
| Uveitis | Human UC-MSCs | Exosomes | Ultracentrifugation | - | - | Reduced experimental autoimmune uveitis in rats Reduced infiltration of Gr-1+, CD161+, CD68+ and CD4+ cells in retina |
[113] |
| Duchenne muscular dystrophy (DMD) | Human Placenta MSCs | Exosomes | Ultracentrifugation | miR-29c | TGF-β, creatine kinase, collagen I, collagen IV, TNF-α, IL-6 ↓ Utrophin ↑ |
Reduced DMD in mice Decreased the tissue fibrosis and inflammation |
[114] |
| Bronchopulmonary dysplasia (BPD) | Human UC-MSCs | Exosomes | Ultracentrifugation | TSG-6 | Neutrophil ↓ | Improved pathology of lung, cardiac and brain in neonatal mice with BPD Reduced pulmonary inflammation and alveolar-capillary leak |
[115] |
| Alzheimer’s disease | Mouse BM-MSCs | Exosomes | Ultracentrifugation | - | TNF-α, IL-1β, IL-6 ↓ IL-10, IL-4, IL-13 ↑ |
Improved cognitive function in transgenic APP/PS1 mice Reduced plaque deposition and Aβ levels Reduced activation of astrocytes |
[116] |
| Post-stroke neuroregeneration | Human BM-MSCs | EVs | PEG6000 precipitation | - | Dcx, NeuN, CD31 ↑ | Improved neurological impairment (motor coordination) and long-term neuroprotection (neuronal survival and cell proliferation) in stroke mice Reduced post-ischemic immunosuppression and lymphopenia Stimulated post-ischemic neurogenesis and angiogenesis |
[117] |
| Diabetic peripheral neuropathy | Mouse BM-MSCs | Exosomes | Ultracentrifugation | miR-17 miR-23a miR-125b |
TNF-α, IL-1β, iNOS, TLR4, IRAK1, p65 ↓ ARG1, IL-10, TGF-β ↑ |
Decreased the threshold for thermal and mechanical stimuli in mice Increased nerve conduction velocity, the number of intraepidermal nerve fibers, myelin thickness, and axonal diameters |
[118] |
| OA | Rabbit BM-MSCs | Exosomes | Ultracentrifugation | - | p-p38, p-ERK ↓ p-AKT ↑ |
Increased chondrocytes viability under IL-1β-induced inflammatory status through activating AKT pathway | [119] |
| Human ES-MSCs | Exosomes | Tangential flow filtration | CD73 | α-SMA, MMP-13, IL-1β, iNOS ↓ PCNA, s-GAG ↑ |
Promoted repair and regeneration of temporomandibular joint OA in rats through the AKT/ERK/AMPK-dependent manner | [120] | |
| Human BM-MSCs | Exosomes | ExoQuick (System Biosciences) |
miR-26a-5p | PTGS, Bcl-2, IL-6, TNF-α, IL-8, IL-1β ↓ Bax, caspase-3 ↑ |
Alleviated OA damage in rats treated with pentobarbital | [121] | |
| Human ES-MSCs | Exosomes | Tangential flow filtration | CD73 | TNF-α, IL-1β ↓ PCNA ↑ |
Induced cartilage repair through the CD73-mediated activation of AKT and ERK pathway | [122] | |
| Intervertebral disc degeneration (IVDD) | Mouse BM-MSCs | Exosomes | Ultrafiltration | - | Caspase-9/3, iNOS, MMP-3/13, caspase-1, IL-1β, TXNIP, NLRP3 ↓ COL2A, SOX9 ↑ |
Prevented progression of IVDD in rabbit Suppressed activation of NLRP3 inflammasome |
[123] |
| Spinal cord injury | Human UC-MSCs | EVs | Ultracentrifugation | IL-1β, IL-6 ↓ | Demonstrated anti-inflammatory and anti-scarring activities in the spinal cord parenchyma in rats | [124] | |
| Rat BM-MSCs | Exosomes | Ultracentrifugation | - | C3, GFAP, TNF-α, IL-1α, IL-1β, p-p65, p-IκBα ↓ | Reduced spinal cord injury-induced A1 astrocytes in rats | [125] | |
| BM-MSCs | Exosomes | Ultrafiltration | - | NO, Bax, caspase-3, TNF-α, IL-1β, IL-6 ↓ Bcl2, VEGF, NF200 ↑ |
Improved functional behavioral recovery in rats Attenuated neuronal cells apoptosis, suppressed glial scar formation Suppressed activation of microglia, A1 neurotoxic reactive astrocytes and neuroinflammation |
[126] | |
| Myocardial infarction | Rat BM-MSCs | Exosomes | Total Exosome Isolation Kit (Invitrogen) |
miR-29, miR-24 | - | Inhibited cardiac fibrosis, inflammation, and improved cardiac function in rat myocardial infarction model | [127] |
| Rat BM-MSCs | Exosomes | ExoQuick (System Biosciences) |
- | NO, Bax, caspase-3/9 ↓ Bcl2 ↑ |
Improved microenvironment of infarcted myocardium in rats through angiogenesis and anti-inflammation | [128] | |
| Acute lung injury (ALI) | Rat BM-MSCs | Exosomes | Exosome extractant (Ribobio Co., Ltd.) |
miR-124-3p | P2X7, TNF-α, IL-6, IL-8 ↓ GSH, SOD ↑ |
Increased survival rate of rats | [129] |
| Rat BM-MSCs | Exosomes | Ultracentrifugation | TNF-α, IL-1β, IL-6, MMP-9 ↓ IL-10, SP-C ↑ |
Attenuated phosgene-induced ALI in rats | [130] | ||
| Rat BM-MSCs | Exosomes | Ultracentrifugation | - | Caspase-3, TNF-α, IL-1β, IL-6, TLR4, NF-κB ↓ | Attenuated ischemia repurfusion (IR)-induced lung injury in rats Decreased apoptosis and inflammation |
[131] | |
| Induced pulmonary fibrosis (IPF) | Human BM-MSCs | Exosomes | Ultracentrifugation | - | CCL2, ARG1 ↓ | Reduce bleomycin-induced IPF in mice Reduced collagen deposition and apoptosis |
[132] |
| Hepatic IR injury | Human iMSCs | Exosomes | Ultrafiltration | TNF-α, IL-6, HMGB1, caspase-3, Bax ↓ GSH, GSH-Px, SOD ↑ |
Suppressed hepatocyte necrosis and sinusoidal congestion Reduced the AST and ALT |
[133] | |
| Liver fibrosis | Human UC-MSCs | Exosomes | Ultrafiltration | - | AST ↑ Collagen I/III, TGF-β 1, p-Smad2 ↓ |
Alleviated hepatic inflammation and collagen deposition in the CCl4-induced fibrotic liver of mice | [134] |
| Acute liver failure | Mouse ASCs | Exosomes | Total Exosome Isolation Kit (Invitrogen) |
miR-17 | TNF-α, IFN-γ, IL-1β, IL-6, IL-18, TXNIP, NLRP3, ASC, caspase-1 ↓ | Ameliorated acute liver failure by reducing ALT and AST in mice Reduced activation of TXNIP/NLRP3 inflammasome in macrophages |
[135] |
| Intestinal bowel disease (IBD) | Human UC-MSCs | Exosomes | Ultracentrifugation | - | TNF-α, IFN-γ, IL-1β, IL-6, IL-17 ↓ TGF-β 1, IL-10 ↑ |
Ameliorated DSS-induced IBD in mice | [136] |
| Necrotizing enterocolitis (NEC) | Mouse BM-MSCs | Exosomes | PureExo (101Bio) |
- | - | Reduced incidence and severity of NEC in premature newborn rats | [137] |
| Abdominal aortic aneurysm | Human UC-MSCs | EVs | Ultracentrifugation | miR-147 | IL-6, IL-17, IFN-γ, IL-23, RANTES, KC, MCP-1, MIP-1α, HMGB1 ↓ | Reduced inflammation and macrophage activation in a mouse abdominal aortic aneurysm model | [138] |
| Perinatal brain injury | Human Wharton’s jelly (WJ)-MSCs | Exosomes | Ultracentrifugation | - | TNF-α, IL-6, IL-1β, CXCL10, IκBα, p-ERK1/2, p-JNK, p-p38 ↓ | Reduced neuroinflammation in rats with perinatal brain injury | [139] |
| Human WJ-MSCs | Exosomes | Ultracentrifugation | - | Mbp, Map 2 ↑ | Reduced neuron-specific cell death in rats with perinatal brain injury | [140] | |
| Traumatic brain injury (TBI) | Rat BM-MSCs | Exosomes | ExoQuick (System Biosciences) |
- | GFAP ↑ | Improved spatial learning in rats with TBI | [141] |
| Human ASCs | Exosomes | ExoQuick (System Biosciences) |
MALAT1 | TNF-α, IL-1β, IFN-γ ↓ | Improved motor behavior in rats with TBI | [142] | |
| Hypoxic-ischemic brain injury | Human BM-MSCs | EVs | PEG6000 precipitation | - | - | Improved function of brain by reducing the total number and duration of seizures in sheep | [143] |
| Urethral stricture | Human UC-MSCs | Exosomes | Ultracentrifugation | miR-146a | α-SMA, collagen I/III, IL-6, IL-1β, IRAK1, TRAF6, NF-κB ↓ | Reduced urethral fibrosis and stricture in rats | [144] |
| Status epilepticus (SE) | Human BM-MSCs | Exosomes | Anion exchange chromatography | - | TNF-α, IL-1β, MCP-1, SCF, MIP-1a, GM-CSF ↓ IL-10, PDGF-B, IL-6, IL-2 ↑ |
Reduced pilocarpine-induced SE in mice Reduced loss of glutamatergic and GABAergic neurons Reduced inflammation in hippocampus |
[145] |
| Human UC-MScs | Exosomes | Ultracentrifugation | - | GFAP, TNF-α, IL-1β ↓ | Ameliorated SE-induced learning and memory impairment in mice | [146] | |
| Retinal IR injury | Human BM-MSCs | EVs | ExoQuick (System Biosciences) |
- | TNF-α, IL-6, caspase-3 ↓ | Reduced neuro-inflammation and apoptosis | [147] |
| Laser-induced retinal injury | Mouse ASCs Human UC-MSCs |
Exosomes | Ultracentrifugation | MCP-1 ↓ | Reduced damage, inhibited apoptosis, and suppressed inflammatory responses in mice | [148] | |
| Sepsis | Mouse BM-MSCs | Exosomes | Ultracentrifugation | miR-223 | TNF-α, IL-1β, IL-6 ↓ | Protected cardiomyocytes from cecal ligation and puncture-induced sepsis in mice through downregulation of SEMA3A and STAT3 | [149] |
| Graft versus Host Disease (GvHD) | Human UC-MSCs | EVs | Ultracentrifugation | - | IL-2, TNF-α, IFN-γ ↓ IL-10 ↑ |
Prevented acute GvHD in a mouse model of allogeneic hematopoietic stem cell transplantation | [150] |
| Human BM-MSCs |
Exosomes | PEG6000 precipitation | - | TNF-α, IL-1β, IFN-γ ↓ | Modulated the patient’s immune cells | [151] |
Abbreviations: AD, atopic dermatitis; ALI, acute lung injury; BPD, bronchopulmonary dysplasia; DMD, Duchenne muscular dystrophy; ES, embryonic stem cell; IBD, intestinal bowel disease; IPF, induced pulmonary fibrosis; IR, ischemia reperfusion; IVDD, intervertebral disc degeneration; JM, jaw bone marrow; MenSCs, menstrual blood derived MSCs; SE, status epilepticus; UC, umbilical cord; WJ, Wharton’s jelly.