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Table 1 List of therapeutic application of some MSC-derived exosomes from different sources in animal models of human disease

From: New therapeutic approaches of mesenchymal stem cells-derived exosomes

Tissue type

MSC origin

Method of exosome isolation

Exosome characterization

Disease focus

Animal type and model

Exosome administration

Related exosome cargo/pathway

Outcome

Refs

Bone marrow

Human

Centrifugation, ultracentrifugation

Determination of total protein concentration (BCA protein assay), TEM, NTA, western blotting (CD9, CD63, CD81, TSG101, and Alix markers)

Liver fibrosis

CCl4 induced liver fibrosis in SD rats

Injection through the tail vein

Wnt/β-catenin pathway

MSC-derived exosomes reduced liver fibrosis in vivo through the Wnt/β-catenin pathway

Exosome treatment reduces the expression of PPARγ, Wnt3a, Wnt10b and β-catenin, what contributed to inhibition of downstream gene expression (WISP1, Cyclin D1) in both hepatic stellate cells and liver fibrosis tissue

[108]

Human

Precipitation (ExoQuick exosome isolation)

Determination of total protein concentration (BCA protein assay), qNano nanopore-based detection, SDS-page (CD9, CD63, CD81), reversed-phase chromatography, Q Exactive mass spectrometry

Traumatic brain injury

Cortical impact Wistar rats model of traumatic brain injury

Intravenously via the tail vein

N.D

Exosomes derived from human BM-MSCs in 2D or 3D cultures improved functional recovery, promoted neurovascular remodeling and reduced neuroinflammation in rats after traumatic brain injury

[114]

Human

Gradient ultracentrifugation, ultrafiltration

Determination of total protein concentration (BCA protein assay), electron microscopy, flow cytometry (CD63)

Bone defects

Calvarial defects in SD rats

Defects treated with hydgogel + EVs

miR-196a, miR-27a, miR-206

In vitro-EVs positively regulated expression of osteogenic genes and osteoblast differentiation

In vivo-EVs stimulated bone formation in rats with calvarial defects

[119]

Porcine

Ultrafiltration

Determination of total protein concentration (Bradford assay), NTA, flow cytometry (CD44 and CD90)

Synovitis

Porcine model of antigen-triggered synovitis

Intra-articular injections

N.D

Exosomes decreased synovial lymphocytes, the downregulated TNF-α transcripts and improved the impulse in exosome-treated joints

[116]

Rat

Ultracentrifugation

Determination of total protein concentration (BCA protein assay), TEM, RT-PCR

Acute kidney injury

Acute kidney injury induced by gentamicin in Wistar rats

Injection into caudal vein

RNAase, RNA carried by the exosomes/microvesicles

BM conditioned media increased the renal function recovery. Protective effects were mediated by the exosome´ RNA in the conditioned media

[86]

Rat

Differential centrifugation

Determination of total protein concentration (BCA protein assay), DLS, confocal microscopy, SEM, TEM, ELISA (CD9), flow cytometry (CD63), western blotting (CD81)

Acute liver injury

Ischemic/reperfusion liver injury and CCl4 induced acute liver injury in rats

Injection through hepatic portal vein

Exosome-rich fractionated secretome

In vitro – exosomes showed antiapoptotic and prosurvival effect, better HepG2 cells recovery and reduced cytotoxicity

In vivo – exosomes improved liver regeneration and recovery from liver injury

[109]

Rat

Precipitation (ExoQuick-TC exosome isolation)

Determination of total protein concentration (BCA protein assay), flow cytometry (CD63), TEM

Myocardial infarction

Acute myocardial infarction in SD rats

Intramyocardial injection

N.D

Exosomes improved cardiac function after ischemic injury

In vitro – exosomes improved the tube formation of HUVEC cells and impaired T-cell function by cell proliferation inhibition

In vivo – exosomes reduced infarct size and retained cardiac systolic and diastolic performance

[111]

Rat

Ultracentrifugation

Electron microscopy

Myocardial infarction

SD rats myocardial ischemia/reperfusion model

Intramyocardial injection into the left ventricular wall

Autophagy machinery

Exosomes inhibited myocardial infarction pathogenesis, probably by autophagy regulation. Exosomes treatment suppressed the expression of Apaf1 (apoptotic protease activating factor 1) and increased the espression of ATG13 (autophagy-related protein13)

[112]

Rat

Multistep centrifugation

Determination of total protein concentration (micro BCA protein assay)

Stroke

Middle cerebral artery occlusion Wistar rats model

Injection into the tail vein

N.D

Exosomes improved neurologic outcome by functional recovery and enhanced neurite remodeling, neurogenesis and angiogenesis. Exosomes systemic treatment improves neurologic outcome, significantly increased the synaptophysin immunoreactive area in ischemic boundary zone

[113]

Mouse

Filtration, differential centrifugation, ultracentrifugation

Determination of total protein concentration (BCA protein assay), DLS, electron microscopy

Cardiac hypertrophy

Transverse aortic constriction mouse model

Intramyocardial injection

N.D

In vitro—exosomes inhibited cell hypertrophy stimulated with angiotensin II in cultured myocytes

In vivo—exosomes significantly protected myocardium against cardiac hypertrophy, inhibited myocardial apoptosis and fibrosis and retained heart function when the pressure was overloaded

[110]

Mouse (ischemic preconditioned)

Precipitation (ExoQuick exosome isolation)

Determination of total protein concentration (BCA protein assay), western blotting (CD9, CD63)

Alzheimer´s disease

Transgenic APP/PS1 mouse model

Injection through lateral caudal vein

miR-21, miR-181c

Exosomes improved memory functions and learning capabilities in mice. Hypoxic MSC-derived exosomes reduced effectively Aβ accumulation, increased the expression of synaptic proteins and enhanced the level of miR-21 in the brains of APP/PS1 mice

[115]

Umbilical cord

Human (Wharton’s jelly) and mouse BM

Precipitation, column size exclusion chromatography, ultracentrifugation

Electron microscopic analysis, determination of total protein concentration (Bradford assay) western blotting (CD63, ALIX, TSG101, CD81, CD9, hsp90, flotillin-1, Dicer), isolation and quantification of microRNAs

Hypoxic pulmonary hypertension

Hypoxia induced pulmonary hypertension in FVB strain mice

N.D

miR-204, miR-17

MSC-derived exosomes were able to inhibit pulmonary hypertension by inihition of hyperproliferative pathways, icluding suppression of the hypoxic activation of STAT3 signaling and the upregulation of the miR-17, whereas it increased lung levels of miR-204

[85]

Human

Ultracentrifugation

Determination of total protein concentration (BCA protein assay), TEM, western blotting (CD9, CD81)

liver fibrosis

CCl4-induced liver fibrosis in mice

Injection into the left and right lobes of livers

(TGF)-b1/Smad signaling pathway

MSC-derived exosomes inhibited EMT and improved CCl4 induced liver fibrosis

In vivo—exosome transplantation reduced TGF-β1 expression, inactivated Smad2 phosphorylation and inverted liver EMT

In vitro – Exosome treatment of HL7702 cells after EMT caused reversed spindle-shaped cells and EMT associated marker expression

[87]

Human

Precipitation (ExoQuick ULTRA EV isolation)

Electron microscopy, NTA, western blotting (TSG101, CD63, CD81), qPCR analysis, sequencing of miRNAs

Acute liver injury

CCl4-induced acute liver injury and endotoxemia in C57BL/6 mice

Injection

miR455-3p

Exosomes enriched in miR-455-3p were capable to inhibited the overactivation of monocyte/macrophages and reduced acute liver injury by inhibiting IL-6-related signaling pathways

[122]

Human

Ultracentrifugation

TEM, western blotting (CD9, CD63, CD81)

Acute kidney injury

Cisplatin-induced acute kidney injury in SD rats

Renal capsule injection

p38MAPK pathway, ERK 1/2 pathway

Exosomes suppressed kidney injury and NRK-52E cell injury by improvement of oxidative stress and cell apoptosis and promotion of cell proliferation through activation of ERK1/2 in vivo and in vitro

[123]

Human

Ultracentrifugation

Determination of total protein concentration (Bradford assay), TEM, flow cytometry

Acute kidney injury

Acute kidney injury model induced by ischemia–reperfusion injury in rats

Intravenous administration

N.D

Exosomes reduced cell apoptosis and improved proliferation 24 h after kidney injury, promoted angiogenesis by inducing VEGF elevation through HIF-1α independent manner

[124]

Human

Differential centrifugation, ultracentrifugation

Determination of total protein concentration (BCA protein assay), western blotting (CD9, HSP70), TEM, NTA

Wound healing and angiogenesis

Skin burn wound model in rats

Subcutaneous injection

Wnt4

In vitro—exosomes elevated endothelial cell proliferation, migration and tube formation

In vivo—exosomes improved angiogenesis in the repair of skin burn injury by delivering Wnt4 to activate Wnt/β-catenin signaling (tissue repair mechanism)

[125]

Human

Ultracentrifugation

Determination of total protein concentration (BCA protein assay), TEM, western blotting (CD9, CD63, CD81, β-catenin, Wnt3a, β-actin)

Fracture healing

Model of femorale fracture in SD rats

Injection of the mix of hydrogel and exosomes into the fracture

N.D

Exosomes participated in the repair of fracture in rats through the Wnt signaling pathway by increasing of β-catenin and Wnt3a protein expressions

[126]

Human

Ultracentrifugation

Determination of total protein concentration (BCA protein assay), NTA, western blotting (CD81)

Wound healing

Skin-defect model in ICR and BALB/c-Ï… mice

Injection of the mix of hydrogel and exosomes around the wound

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

Exosomes enriched in specific microRNAs (miR-21, -23a, -125b, and -145) inhibited myofibroblast formation, inhibited TGF-β2, TGF-βR2 and SMAD2 pathway and accordingly suppressed the expression of α-SMA gene and reduced collagen I deposition. Significant role of exosomes for anti-scarring ability and the myofibroblast-suppressing was showed both in vitro and in vivo by blocking miRNAs inside the exosomes

[127]

Human

Ultracentrifugation

TEM, determination of total protein concentration (BCA protein assay), NTA, western blotting (CD9, CD63, CD81)

Inflammatory bowel disease

DSS-induced inflammatory bowel disease mouse model

Injection through the tail vein

N.D

Exosomes could improve inflammatory bowel disease

In vitro – coculture with exosomes suppressed the expression of iNOS and IL-7 in mouse enterocelia macrophages

In vivo – exosomes reduced the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6) and increased the expression of anti-inflammatory cytokine (IL10)

[128]

Human

Ultracentrifugation

Determination of total protein concentration, TEM, Zetasizer, western blotting (CD9, CD63, CD81)

Colitis

Colitis induction in C57BL/6 mice

Intraperitoneal injection

N.D

In vitro – exosomes decreased pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β) concentration and enhanced the secretion of anti-inflammatory cytokines (TGF-β1, IL-10)

In vivo – exosomes showed therapeutic activity in experimental colitis via suppressing inflammation machinery, improved clinical symptoms and histological severity

[90]

Adipose

Human

Ultracentrifugation

Determination of total protein concentration (Bradford assay), TEM, NTA, SIOS,

Alzheimer’s disease

N.D

N.D

Neprilysin

Exosomes secrete enzymatically active neprilysin. Transfer of exosomes to N2a cells significantly decreased both the intracellular and extracellular Aβ40 and Aβ42 levels

[133]

Pig

Ultracentrifugation

NTA, TEM, western blotting (CD9, CD29, CD63), RT PCR (mRNA content of IL-10)

Renal inflammation

Metabolic syndrome and renal artery stenosis model in domestic pigs

Intrarenal delivery

IL-10

Exosomes reduced renal inflammation, enhanced the reparative macrophages number and increased expression of IL-10. Exosomes were able to reduce renal fibrosis and to improve stenotic kidney function

[130]

Rat

Ultrafiltration, ultracentrifugation

Determination of total protein concentration (BCA protein assay), TEM, western blotting (CD9, CD63, HSP70, CD81)

Ischemic heart disease

Myocardial ischemia/reperfusion model in SD rats

Infusion through the tail vein

N.D

Exosomes protected ischemic myocardium from ischemia/reperfusion injury through the Wnt/β-catenin signaling pathway activation

In vitro – exosomes reduced cell apoptosis and the expression of Bax, improved cell viability and the expression of Bcl-2 and Cyclin D1 in hypoxia/reoxygenation-induced H9c2 cells

In vivo – exosomes significantly reduced ischemia/reperfusion-induced myocardial infarction, it was showed decrease in serum levels of creatine kinase-myocardial band, lactate dehydrogenase, and cardiac troponin I. After exosome treatment was observed attenuation of ischemia/reperfusion-induced apoptosis accompanied by the increase of Bcl-2 and decrease of Bax, and inhibition of Caspase 3 activity in rat myocardium

[131]

Mouse

Precipitation and magnetic beads purification (MagCapture Exosome Isolation)

Determination of total protein concentration (BCA protein assay), NTA, TEM, western blotting (CD29, CD63)

Acute myocardial infarction

N.D

N.D

N.D

Exosomes reduced apoptosis in myocardial cells subjected to oxidative stress in vitro

(132)

  1. N.D, not defined in the given reference; TEM, transmission electron microscopy; NTA, nanoparticle tracking analysis; SIOS, scanning ion occlusion sensing; EMT, epithelial-mesenchymal transition; DLS, Dynamic light scattering; SEM, scanning electron microscopy