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Table 1 Anti-fibrotic effect of MSC-EVs in different models

From: Mesenchymal stem cell-derived extracellular vesicles in therapy against fibrotic diseases

Organ

Model

Animal

In vitro model

Administration

Dosage

Source of EVs/Exos/MVs

Cargo in EVs

Mechanism

Effect

Refs.

Lung

BLM

C57BL/6 J mice

MLE-12 cells with TGF-β1

Tail vein

0.5 mg/kg/day for 7 days

MenSC-Exos

miR-let-7

↓LOX1

Regulating ROS, mtDNA damage, and NLRP3 inflammasome activation

[12]

 

BLM

C57BL/6 mice

LL29

Tail vein

100 μg

BMMSC–EVs

miR-29b-3p

↓FZD6

Inhibiting fibroblast proliferation, migration, and differentiation

[13]

 

BLM

C57BL/6 mice

LL29

Tail vein

100 μg

BMMSC–EVs

miR-186

↓SOX4 and DKK1

Restraining fibroblast activation

[14]

 

BLM

C57BL/6 mice

 

Tail vein

8.6 × 108 particles

BMMSC–EVs

  

Modulating monocyte phenotypes

[15]

 

Radiotherapy

C57 mice

 

Tail vein

100 μg

hpMSC-EVs

miR-214-3p

↓ATM/P53/P21

 

[16]

 

Pulmonary artery hypertension

Wistar rats

Pulmonary artery endothelial cells

Tail vein

25 µg for 3 days

huMSC-Exos

 

Wnt5a/BMP

Inhibiting EndMT

[17]

 

PM2.5

SD rats

Type II alveolar epithelial cells

Intratracheal instillation

2.5 ~ 2.8 × 1010 particles

ADMSC-EVs

miR-let-7d-5p

↓TGF-βRI

 

[18]

 

Lipopolysaccharide

C57BL/6 mice

MLE-12 cells

Tail vein

70 μg

BMMSC-Exos

miR-23a-3, miR-182-5p

↓NF-κB and hedgehog pathways via silencing Ikbkb and Usp5

Reversing EMT

[19]

Liver

CCl4

Mice

HL7702 with TGF-β1

Right lobes of livers

250 mg

huMSC-Exos

 

↓TGF-β1/Smad signalling pathway

Inhibiting EMT

[20]

 

CCl4

SD rats

Human HSCs line LX2

  

CPMSC-Exos

miR-125b

↓Hedgehog signalling

Suppressing activation of HSCs

[21]

 

CCl4

C57BL/6 J mice

HSCs with TGF-β

Tail vein

 

ADMSC-EVs

miR-150-5p

↓CXCL1

 

[22]

 

CCl4

SD rats

HSCs

Tail vein

250 mg

BMMSC-Exos

 

↓Wnt/β-catenin signalling pathway

Inhibition of HSCs

[23]

 

NASH; CCl4

SD rats

HSCs and KCs

Intravenous

15/20 μg/kg

AMSC-EVs

 

↓LPS/TLR4 signalling pathway

↓Activation of HSCs and Kupffer cells

[24]

 

NASH

SCID mice

 

Tail vein

2.5 × 108 particles

HLSC-EVs

251 proteins

 

↓Inflammation and cytokine pathways

[25]

Kidney

I/R

C57BL/6 mice

mTECs

Tail vein

100ug

ADMSC-Exos

 

↑Sox9

 

[26]

 

STZ

Babl/c mice

HK-2

Tail vein

1.5 mg/kg

huMSC-MVs

miR-451a

↓P15 and P19

Inhibiting EMT

[27]

 

STZ

NSG mice

 

Intravenous

1 × 1010 particles

HLSC/BMMSC-EVs

miRNAs

Fibrosis-related genes

 

[28]

 

Aristolochic acid

NSG mice

mTECs

Intravenous

1 × 1010 particles

BMMSC-EVs

 

↓α-SMA, TGF-β1 and Col1a1 genes

 

[29]

 

High glucose

 

MPC5 cells

  

ADMSC-Exos

miR-215-5p

↓ZEB2

Reversing EMT

[30]

 

UUO

C57BL/6 J mice

NRK52E

  

BMMSC-Exos

miR-let7c

↓TGF-βR1

 

[31]

 

UUO

SD rats

 

Tail vein

10 mg/kg

huMSC-Exos

CK1δ/β-TRCP

↓YAP

 

[32]

 

UUO

SD rats

NRK-52E cells with TGF-β1

Renal artery

200 μg

huMSC-EVs

 

↓ROS-mediated P38MAPK/ERK signalling pathway

 

[33]

 

UUO

SD rats

HK-2 cells with TGF-β1

Intravenous

0.5 mg/kg

BMMSC-EVs

MFG-E8

↓RhoA/ROCK signalling

 

[34]

Heart

TAC

C57BL/6 mice

NRVCs with AngII

Intramyocardial

20 μL

BMMSC-Exos

  

↑Senescence of myofibroblasts

[35]

 

MI

Mice

HL-1 cardiac muscle cells

 

0.5 μmol

BMMSC-Exos

miR-19a/19b

  

[36]

 

MI

Rats

H9c2 cells with hypoxia

Inferior vena cava

2.5 × 1012 particles

ADMSC-Exos

 

↑S1P/SK1/S1PR1 signalling

 

[37]

 

MI

C57BL/6JNifdc mice

Cardiomyocytes with OGD

Boundary area of the infarcted cardiac

100 μg

ADMSC-Exos

miR-671

TGFβR2/Smad2

 

[38]

Skin

Full-thickness skin defect

ICR and nude mice

Fibroblasts with TGF-β

Inject around the wound

100 mg/ml

huMSC-Exos

miR-21, -23a, -125b, -145

↓TGF-β/Smad2 pathway

↓Myofibroblast differentiation

[39]

 

Full-thickness skin defect

BALB/c mice

Dermal fibroblasts

Intravenous

200 μL

ADMSC-Exos

 

↑MMP3 expression via ERK/MAPK pathway

Regulating ratios of type III: type I collagens, TGF-β3: TGF-β1, and MMP3:TIMP1 and fibroblast differentiation

[40]

 

Full-thickness skin defect

C57BL/6 mice

 

Intradermal

10 μg

MenSC-Exos

  

↓Col1: Col3 ratio

[41]

 

Full-thickness skin defect

BALB/c mice

HSFs

Subcutaneous

70 μg

ADMSC-Exos

miR-192-5p /

Regulating Smad signalling pathway via IL-17RA

↓The proliferation and migration of HSFs, decreased collagen deposition

[42]

 

Sclerodermatous cGVHD

BALB/c mice

 

Intraperitoneal

100 μg

huMSC-EVs

 

↓TGF-β/smad2

↓The activation of macrophages and B cells immune response

[43]

Uterus

IUA

ICR mice

Endometrial epithelial cells

Uterine cavity

100μL

BMMSC-Exos

miR-29a

 

↑Endometrial repair

[44]

 

IUA

SD rats

Endometrial stromal cells

Tail vein

 

BMMSC-Exos

miR-340

↓col1α1, TGF-β1 and α-SMA expression

 

[45]

 

IUA

Rabbits

Endometrial epithelial cells with TGF-β1

Muscle walls of the uterus

50 μg

BMMSC-Exos

 

↓TGF-β1/Smad pathway

Reverse EMT

[46]

Tendon

Tendon adhesion

SD rats

Fibroblast cells with TGF-β1

Subcutaneous

200 μg

huMSC-Exos

miR-21a-3p

↓p65

 

[47]

Colon

TNBS

SD rats

IEC-6 Cells with TGF-β1

Intravenous

10 μg/day for 6 days

BMMSC-MVs

miR-200b

↓ZBE1 and ZEB2

Inhibiting EMT

[48]

  1. MSCs, mesenchymal stem cells; EVs, extracellular vesicles; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; Exos, exosomes; MVs, microvesicles; BLM, Bleomycin; EndMT, Endothelial-mesenchymal transition; EMT, epithelial mesenchymal transition; CCl4, carbon tetrachloride; HSCs, hepatic stellate cells; NASH, nonalcoholic steatohepatitis; I/R, ischemia/reperfusion; STZ, streptozotocin; UUO, unilateral ureteral obstruction; TAC, transverse aortic constriction; MI, myocardial infarction; HSFs, hypertrophic scar-derived fibroblasts; IUA, intrauterine adhesion