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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-υ 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