Table 2 Therapeutic effects of mesenchymal stem cell-derived exosomes in different diseases in preclinical experimental models

Cardiovascular diseases

hBM-MSC

HUVEC cell

Improved proliferation, migration, and tube formation of endothelial cells in vitro

Promoted neoangiogenesis in vitro and in vivo

[50]

Rat MI

Improved cardiac indices, i.e. cardiac systolic/diastolic performance and blood flow

Reduced infarct size in vivo

mBM-MSC

Mouse HPH

Inactivated STAT3 pathway

Reduced vascular remodeling and HPH

[51]

Decreased the levels of miR-17 superfamily

Increased miR-204 levels in lung cells

Repressed the hypoxic pulmonary influx of macrophages and the induction of MCP1 and HIMF

rBM-MSC overexpressing CXCR4

Neonatal CM

Upregulated IGF1α and pAkt levels, inhibited caspase 3, and promote VEGF expression and tubulogenesis in vitro

Increased angiogenesis

[52]

Rat MI

Reduced infarct size

Improved cardiac remodeling

rBM-MSC

HUVEC cell

Enhanced tube formation by HUVEC cells

Decreased infarct size; preserved cardiac systolic and diastolic performance; enhanced the density of new functional capillary and blood flow recovery in vivo

[53]

Rat MI

Compromised T cell function by impeding cell proliferation in vitro

mBM-MSC

Mouse MI

miR-22-enriched exosomes were secreted after MI which reduced cardiomyocyte apoptosis by direct targeting of Mecp2

Reduced infarct size and cardiac fibrosis in vivo

[55]

rBM-MSC overexpressing GATA-4

Neonatal rat CM

miR-221-enriched exosomes reduced the expression of p53 while upregulating PUMA

[56]

Expression of PUMA was greatly declined in CM cocultured with MSC

rBM-MSC overexpressing GATA-4

Neonatal rat CM

Increased CM survival, reduced CM apoptosis, and preserved mitochondrial membrane potential in vitro

Exosomal miR-19a could restore cardiac contractile function and decreased infarct size in vivo

[57]

Rat MI

Exosomal miR-19a downregulated PTEN and triggered the Akt and ERK signaling pathways

mBM-MSC

HUVEC cell

Enhanced the proliferation, migration and tube formation in vitro

Promoted angiogenesis and cardiac function in vivo

[58]

Mouse MI

The pro-angiogenic effect of exosomes is probably associated with a miR-210-Efna3 dependent mechanism

hEn-MSC

Neonatal CM

Overexpression and shuttling of exosomal miR-21 was attributed to suppression of PTEN, stimulation of Akt, along with Bcl-2 and VEGF upregulation

Restored cardiac function and reduced infarct size

[59]

HUVEC cell

Rat MI

rBM-MSC

Cardiac stem cell

Triggered proliferation, migration, and angiotube formation in vitro probably mediated by a set of microRNAs

Reduced cardiac fibrosis in vivo

[60]

Rat MI

Enhanced capillary density

Restored long‐term cardiac function

Kidney diseases

hBM-MSC

mTEC

Exosomal mRNAs encoding CDC6, CDK8 and CCNB1 influenced cell cycle entry

Improved renal function and morphology

[61]

Mouse AKI

Exosomal miRNAs regulated proliferative/anti-apoptotic pathways and growth factors (HGF and IGF1) that led to renal tubular cell proliferation

hAD-MSC overexpressing GDNF

HUVEC cell

Triggered migration and angiogenesis in vitro

Reduced peritubular capillary rarefaction and renal fibrosis scores in vivo

[62]

Mouse ureteral obstruction

Conferred apoptosis resistance

Enhanced Sirtuin 1 signaling and p-eNOS levels

hBM-MSC

Rat IRI

Enhanced TEC proliferation and survival possibly via exosomal miRNA and mRNA molecules regulating renoprotective signaling routes

[63]

Gl-MSC

Mouse IRI

Activated TEC proliferation

Ameliorated kidney function

[64]

Reduced the ischemic damage post IRI

mK-MSC

HUVEC cell

Promoted cell proliferation in vitro and in vivo

Selective engraftment in ischemic tissues and significant improvement of renal function

[65]

Mouse IRI

Improved endothelial tube formation on growth factor reduced Matrigel

Expressed pro-angiogenic mRNA molecules encoding bFGF, IGF1 and VEGF

rAD-MSC

Rat IRI

Decreased expression of TNFα, NF-κB, IL1β, MIF, PAI1, Cox2 pro-inflammatory molecules

Reduced creatinine and BUN level, and improved renal function

[66]

Reduced the levels of NOX1, NOX2, and oxidized protein

Downregulated Smad3 and TGFβ fibrotic proteins

Enhanced Smad1/5 and BMP2 anti-apoptotic proteins

Upregulated CD31, vWF, and angiopoietin angiogenic biomarkers

Enhanced mito-Cyt C levels

rBM-MSC

Rat AKI

Enhanced IL10 levels

Decreased creatinine, urea, FE_Na, necrosis, apoptosis

[67]

Downregulated TNFα and IL6 expression

Increased cell proliferation

hWJ-MSC

HUVEC cell

Repressed NOX2 and ROS

Reduced fibrosis

[68, 69]

NRK-52E cell

Decreased apoptosis and sNGAL levels

Improved renal function

Rat IRI

Enhanced cell proliferation. Upregulated Nrf2/antioxidant response element and HO1 in vitro and in vivo

hWJ-MSC

NRK-52E cell

Upregulated autophagy-related genes such as ATG5, -7, and LC3B in vitro and in vivo

Improved renal function in vivo

[70]

Rat AKI

Induced mitochondrial apoptosis

Inhibited secretion of TNFα, IL1β, and IL6 pro-inflammatory cytokines in vitro

hWJ-MSC

NRK-52E cell

Reduced apoptosis and necrosis of proximal kidney tubules

Decreased BUN and creatinine levels

[71]

Rat AKI

Decreased production of tubular protein casts through anti-oxidation and anti-apoptosis pathways in vitro and in vivo

Promoted cell proliferation by activating the ERK1/2 pathway

hBM-MSC

PTEC cell

Promoted cell proliferation by carrying IGF1 receptor mRNA, but not IGF1 mRNA

[72]

Liver diseases

hWJ-MSC

HL7702 cell

Suppressing epithelial-to-mesenchymal transition in vitro and in vivo

Reduced LF

[73]

Mouse LF

Inactivated the TGFβ1/SMAD2 pathway

Alleviated hepatic inflammation and collagen deposition

Recovered serum AST function

Reduced collagen type I and III

hESC-MSC

TAMH, THLE-2, and HuH-7 cells

Upregulated PCNA and Cyclin D1 cell cycle proteins and anti-apoptotic Bcl-xL gene

Recovered ALI

[74]

Mouse ALI

hCP-MSC

Rat LF

Exosomal miR-125b blocked Smo production and inactivated Hedgehog signaling mode

Reduced expansion of progenitors and regressed LF

[75]

MiR‐122‐modified-hAD-MSC

Mouse LF

Exosomal miR-122 regulated the expression of IGF1R, Cyclin G1 (CCNG1) and P4HA1, which suppress HSC activation and collagen maturation

Suppressed LF development

[76]

Reduced the serum levels of HA, P‐III‐P, ALT, AST and liver hydroxyproline content

mBM-MSC

Mouse ALI

Reduced pro-inflammatory cytokines and apoptosis

Decreased the serum levels of ALT and liver necrotic areas

[77]

Upregulated anti-inflammatory cytokines

Triggered the number of Tregs

hWJ-MSC

Mouse ALI

Exosomal GPX1 cleared H₂O₂ and reduced apoptosis

Treated liver failure

[78]

h/mBM-MSC

Mouse LI

Exosomal Y-RNA-1 modulated cytokine expression and reduced peripheral inflammatory responses and apoptosis

Reduced hepatic injury and increased survival

[79]

Neurological diseases

hBM-MSC

Mouse stroke

Enhanced angioneurogenesis

Recovered postischemic neurological injury

[80]

Attenuated postischemic immunosuppression (i.e., B cell, NK cell and T cell lymphopenia) in the peripheral blood

Presented long term neuroprotection. Reduced motor coordination impairment

rBM-MSC

Rat stroke

Increased synaptophysin-positive regions in the ischemic boundary zone

Promoted neurovascular remodeling, axonal density and functional recovery

[81]

Enhanced the number of newly formed doublecortin and vW

rBM-MSC

Rat stroke

Exosomal miR-133b decreased the expression of connective tissue growth factor and ras homolog gene family member A

Resulted in neurite remodeling and stroke recovery

[82]

rBM-MSC overexpressing miR-17–92 cluster

Rat stroke

Inhibited PTEN and activated the downstream proteins, protein kinase B and glycogen synthase kinase 3β

Improved neurogenesis, neurite remodeling/neuronal dendrite plasticity and oligodendrogenesis

[83]

hBM-MSC

Rat BI

Attenuated inflammation-induced neuronal cellular degeneration

Improved long-lasting cognitive functions

[84]

Decreased microgliosis and prevented reactive astrogliosis

Restored short term myelination deficits and long term microstructural abnormalities of the white matter

hBM-MSC

Ewe BI

Reduced the neurological sequelae

Promoted brain function via decreasing the total number and duration of seizures

[85]

Did not affect cerebral inflammation

Preserved baroreceptor reflex sensitivity

rBM-MSC

Rat TBI

Enhanced angiogenesis, the number of newborn immature and mature neurons, and decreased neuroinflammation

Improvement of spatial learning

[86]

Recovered sensorimotor function

rB-MSCs

Mouse TBI

Suppressed the expression of pro-apoptotic Bcl-2-associated X protein, TNFα and IL1β

Reduced the lesion size and recovering neurobehavioral performance

[87]

Upregulated anti-apoptotic protein B-cell lymphoma 2

Modulated microglia/macrophage polarization

rBM-MSC

Rat SCI

Regulated macrophage function by targeting M2-type macrophages in the injured sites

[88]

rBM-MSC

Rat SCI

Reduced the proportion of A1 astrocytes via blocking the nuclear translocation of the NF-κB p65

Reduced lesion area

[89]

Reduced the percentage of p65 positive nuclei in astrocytes and TUNEL-positive cells in the ventral horn

Downregulated IL1α, IL1β and TNFα

Increased the expression of myelin basic protein, synaptophysin and neuronal nuclei

hBM-MSC

Rat SCI

Showed anti-inflammatory responses in the damaged tissue and disorganization of astrocytes and microglia

Improved locomotor activity

[90]

mBM-MSC

Mouse AD

Normoxic MSC exosomes: Decreased plaque deposition and Aβ levels

Normoxic MSC exosomes: Recovered cognition and memory impairment

[91]

Reduced the activation of astrocytes and microglia

Preconditioned MSC exosomes: Improved learning and memory capabilities

Downregulated TNFα and IL1β and upregulated IL4 and IL10

Deactivated STAT3 and NF-κB

Preconditioned MSC exosomes: Reduced plaque deposition and Aβ levels

Upregulated growth-associated protein 43, synapsin 1, and IL10

Decreased the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNFα, IL1β

Deactivated STAT3 and NF-κB

Enhanced miR-21 levels

hAD-MSC

Mouse N2a cell

Exosomes carried enzymatically active neprilysin and decreased both secreted and intracellular Aβ levels

[92]

hDP-MSC

ReNcell VM human neural stem cell

Rescued dopaminergic neurons from apoptosis via inducing 6-hydroxy-dopamine

[93]

Wound healing

hWJ-MSC

EA.hy926 and HFL1 cells

Triggered propagation, migration, and tube formation in vitro

Improved wound healing in vivo

[94]

Rat skin burn

Stimulated β-catenin nuclear translocation

Upregulated proliferating cell nuclear antigen, cyclin D3, N-cadherin, and β-catenin

Downregulated E-cadherin

hWJ-MSC

Dermal fibroblast and HEK293T cell

Exosomal miR-21, ‐23a, ‐125b, and ‐145 inhibited scar formation and myofibroblast accumulation through TGFβ2/SMAD2 pathway blockade and reduction of collagen deposition in vitro and in vivo

[95]

Mouse skin-defect

hiPSC-MSC

HUVEC cell

Upregulated angiogenesis-related biomolecules

Increased microvessel density and blood perfusion

[96]

Mouse femoral artery excision

hWJ-MSC

Rat skin burn

Upregulated collagen I, PCNA and CK19

Resulted in rapid in vivo re-epithelialization

[97]

Exosomal Wnt4 contributed to β-catenin nuclear translocation and promotion of skin cell propagation and migration

Activated AKT pathway which reduced heat stress-induced apoptosis in vivo

hWJ-MSC

Rat skin burn

Decreased TNFα and IL1β levels and increased IL10 levels

[98]

Exosomal miR-181c decreased inflammation via suppressing the TLR4 signaling route

hAD-MSC

HUVEC cell

Promoted angiogenesis in vitro and in vivo

[99]

Immunodeficient mouse

Exosomal miR-125a acted as a pro-angiogenic factor by downregulating DLL4 and regulating the generation of endothelial tip cells

hiPSC-MSC

HUVEC cell and dermal fibroblast

Promoted collagen maturity and neoangiogenesis

Enhanced re-epithelialization

[100]

Rat skin wound

Triggered cell proliferation and migration in vitro

Decreased scar size

Increased type I, III collagen and elastin mRNA expression and secretion and tube formation in vitro

hBM-MSC

Diabetic wound and normal fibroblasts

Promoted fibroblast propagation and migration

[101]

Enhanced tube formation

Triggered Akt, ERK, and STAT3 signaling pathways

Upregulated HGF, IGF1, NGF and SDF1

Other diseases

hWJ-MSC and hBM-MSC

Mouse BPD

Triggered pleiotropic effects on gene expression related with hyperoxia -induced inflammation

Relieving BPD, hyperoxia-associated inflammation, fibrosis, pulmonary hypertension and pulmonary vascular remodeling in the lung tissue

[102]

Modulated the macrophage phenotype fulcrum, repressing the M1 state and promoting a M2-like state

hAD-MSC

Mouse atopic dermatitis

Decreased the levels of eosinophils, IgE, CD86⁺ and CD206⁺ cells, and infiltrated mast cells

Ameliorated atopic dermatitis in vivo

[103]

hBM-MSC

C2C12 and HUVEC cells

Exosomal miR-494 improved angiogenesis and myogenesis in vitro and in vivo

Resulted in muscle regeneration

[104]

Mouse muscle injury

hBM-MSC and hWJ-MSC

hPBMC

Enhanced the number of Tregs in vitro

Decreased educed the mean clinical score of EAE mice

[105]

Mouse EAE

Decreased PBMC proliferation and levels of pro-inflammatory Th1 and Th17 cytokines inclusive of IL6, IL12p70, IL17AF, and IL22

Decreased demyelination and neuroinflammation

Enhanced levels of indoleamine 2,3-dioxygenase