Table 5.
Recent advances in the applications of exosomes in regenerative medicine.
| Disorder | Exosome source | Aim of using exosomes | Regenerative medicine methodology | In vivo/In vitro | Ref. |
|---|---|---|---|---|---|
| Heart | Cardiosphere-derived cells | Improving cardiac functions after myocardial hypertrophy treatment | Enhancing accumulation of exosomes by expressing heart homing peptide, miRNA-148a delivery, and inhibition of β-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT | In vitro, in vivo | [313] |
| Enhancing endocytosis of exosomes by binding cardiomyocyte-specific peptide | Ligation of modified exosomes to cardiomyocyte-specific peptide | In vitro, in vivo | [314] | ||
| Modifying injured skeletal and cardiac muscle function | Transcriptome profile reversion and increasing cardio myogenesis | In vivo | [315] | ||
| Improving the cardiac functions in DMD patients | Reduction in collagen I and III levels, increase in cardiomyocyte proliferation and MYOD levels, restoration of dystrophin levels | In vivo | [316] | ||
| Cardiac regeneration | Derived exosomes enriched in miR-146a, enhancing cell survival and angiogenesis | In vitro, in vivo | [317] | ||
| Hypoxia-pretreated Cardiosphere-derived cells | Cardio-protection | Upregulation miR-210, miR-130a, and miR-126 and angiogenesis | In vitro | [318] | |
| MSCs | Cardio-protection after ischemic injury | HSF1 overexpressing MSCs and isolating miRNAs' enriched exosomes | In vivo | [319] | |
| Reduction of infarct size | Increasing ATP and NADH levels and phosphorylated-Akt and phosphorylated-GSK-3β, and decreasing oxidative stress and phosphorylated-c-JNK | In vivo | [320] | ||
| Human UCMSCs | Myocardial protection by preventing apoptosis of myocardial cells | Increasing in Bcl-2 expression | In vitro, in vivo | [321] | |
| Cardiac regeneration after acute myocardial infarction | Exosomal TGF-β3 could expand angiogenesis, diminish myocardial fibrosis, and preserve the heart function | In vitro, in vivo | [322] | ||
| Cardiac progenitor cells | Apoptosis inhibitor | Enriching in miRNAs that inhibit apoptosis or help the formation of the endothelial tube such as miR-210, miR-132, miR-146a-3p, and miR-181 | In vitro, in vivo | [323] | |
| Cardiomyocytes | Angiogenesis | HSP20 association with Akt and ERK signaling pathways and VEGFR2 activation | In vitro, in vivo | [324] | |
| HT1080 and cardiosphere-derived cells | Targeting exosomes by cardiac homing peptide | Target delivery of infracted heart, improve survival of neonatal rat cardiomyocytes, and vascularization | In vitro, in vivo | [325] | |
| Atorvastatin-pretreated MSCs | Cardio-protection | IL-6 and TNF-α inhibition, regulation of miR-675 expression, activation of vascular endothelial growth factor, improve lncRNA H19 expression | In vitro, in vivo | [326] | |
| Transduced MSCs with GATA-4 | The effects of GATA-4 transduction on levels of miRs | Increasing in miR-19a expression, decreasing in PTEN levels, activation of Akt and ERK signaling | In vitro, in vivo | [327] | |
| Blood | Cardio-protection | HSP70 and toll-like receptor 4 communication and HSP27 activation | Ex vivo | [328] | |
| Central nervous system | Rat multipotent MSCs | Improve hippocampal neurogenesis in rats of TBI | Exosomes carrying miRNA-124 are correlated with M2 polarization of microglia via the TLR4 pathway | In vivo | [329] |
| Stimulate neurite outgrowth after stroke | Exosomal transfer of miRNA-133b to neural cells | In vitro | [330] | ||
| Promote endogenous angiogenesis and neurogenesis and reduce neuroinflammation | Correlated with suppression of activated microglia and macrophages by exosomes | In vivo | [331] | ||
| Human BMSCs | Promote endogenous angiogenesis and neurogenesis and reduce neuroinflammation | Correlated with suppression of activated microglia and macrophages by exosomes | In vivo | [332] | |
| Promote retinal ganglion cells' survival and regeneration of their axons | Knockout of Argonaute-2, a key miRNA effector molecule | In vitro, in vivo | [333] | ||
| Human UCMSCs | Inhibition neural apoptosis, reduced inflammation and promoted neurological regeneration in rats after TBI. | Suppression of NF-kB signaling pathway | In vivo | [334] | |
| Peripheral nervous system | Rat ASCs | PNS regeneration, by reducing apoptosis | Upregulation the anti‐apoptotic Bcl‐2 mRNA expression and downregulating the pro‐apoptotic Bax mRNA expression | In vitro | [335] |
| Promote regeneration of the myelin sheath | Kpna2 downregulation via miR-25b | In vitro, in vivo | [336] | ||
| Murine ASCs | Enhancing nerve regeneration after nerve crush injury | Might be correlated with HDAC, APP and ITGB1, candidates involved in exosomes-mediated nerve regeneration | In vivo | [337] | |
| Modulate the microenvironment in neuro-inflammatory and neurodegenerative disorders. | Associated with inhibition of apoptotic cascade | In vitro | [338] | ||
| Human ASCs | Promote neural survival and proliferation | MALAT1 protein mediates the splicing of pkcδII, an anti-apoptotic protein | In vitro | [339] | |
| Rat BMSCs | Stimulate peripheral nerves' regeneration | Closely related to expression of VEGFA and S100b genes via a miRNA-mediated mechanism | In vitro, in vivo | [340] | |
| Dedifferentiated Schwann cells | Increased axonal regeneration in vitro and enhanced regeneration after sciatic nerve injury in rat | Inhibition of GTPase Rhoa activity, thereby inhibiting axonal elongation and promoting growth cone collapse after activation | In vitro, in vivo | [341] | |
| Endothelial cells | Boosting and maintaining the repair phenotypes of Schwann cells | Stimulation of PI3K/AKT/PTEN signaling pathway | In vitro, in vivo | [342] | |
| Gingiva-derived MSCs | Peripheral nerve regeneration | Closely related to activation of c-JUN activity, and upregulation of Notch1, GFAP and SOX2 | In vivo | [343] | |
| Pericytes | Promote angiogenesis and cavernous nerve regeneration under diabetic conditions | Might be correlated with Lcn2 which acts activating MAP kinase and PI3K/Akt and suppressing P53 signaling | In vivo | [344] | |
| Skin | ASCs | Molecular mechanism in skin wound healing | Long noncoding RNA H19 targets miR-15 b y and this, in turn, targets SOX9, which activates the Wnt/β-catenin pathway | In vitro, in vivo | [345] |
| Skin wound healing | miR-19b exosome regular the TFG-β pathway by CCL1 | In vitro, in vivo | [346] | ||
| Photoaging by UVB irradiation | Upregulate the expression of type I collagen mRNA and downregulate the expression of type III collagen, MMP-1, and MMP-3 mRNA | In vitro, in vivo | [347] | ||
| Inflammatory response and skin wound healing | Reduces the lipopolysaccharide-induced inflammatory mRNA and M1-type macrophage-specific marker expression and increases cytokines IL-10, VEGF, and TGF-β and M2-type macrophage marker Arg1 expression | In vitro, in vivo | [348] | ||
| Human platelet lysate | Skin aging | Reduces MMP-1 levels and, consequently, increases collagen levels | In vivo | [349] | |
| Bovine milk | Aging and skin hydration | Hydrating effect on keratinocytes through the increase of filaggrin and CD44 receptor. Hydrating effect on fibroblasts through the increase of HAS2. Prevents the decrease of type II and III collagen after exposure to UVB rays. |
In vitro, in vivo | [350] | |
| Bovine colostrum | Improves on aging and UV-induced damage to various skin cells | Antioxidant effect on keratinocytes by reducing intracellular ROS through the glutathione oxidation pathway. Effect on elasticity by decreasing MMP2 expression. | In vitro | [351] | |
| Solanum tuberosum | Photoaging by UVB irradiation | Inhibition action on MMP1, 2, and 9, as well as on the cytokines IL6 and TNF-α in keratinocytes. Antioxidant effect through the expression of glutathione S-transferase α 4 | In vitro | [352] | |
| Lactobacillus plantarum | Skin aging | Decrease MMP-1 mRNA expression and elastase activity and increase filaggrin mRNA expression and HAS2 protein expression. | In vitro, in vivo | [353] | |
| Apple | Skin aging and reparation | Negative effect on the activity of Toll-like Receptor 4 and NF-κB pro-inflammatory pathway | In vitro | [354] | |
| Human amniotic fluid-derived stem cells | Skin wound healing | Decreased secretion of inflammation-associated cytokines through CXCR4 | In vivo | [355] | |
| Human UCMSCs | Molecular mechanism in skin wound healing | PI3K/AKT pathway is regulated by phosphatase and tensin homolog | In vitro | [356] | |
| BMSCs | Photoaging by UVB irradiation | Suppressed the mRNA of MMP-2 | In vitro | [357] | |
| Hypoxia-pretreated ASCs | Regenerative effects in UVB-induced skin injury | circ-Ash 1l targets miR-700-5p and GPX4, and miR-700-5p target GPX4. | In vitro, in vivo | [358] | |
| Epidermal stem cells | Skin wound healing | May inhibit the differentiation of fibroblasts to myofibroblasts via suppressing TGF-β1 expression via miR-425-5p and miR-142-3p | In vivo | [359] | |
| Human dermal fibroblast | Photoaging by UVB irradiation | Increased procollagen type I expression and a decrease in MMP-1 expression, mainly through the downregulation of TNF-α and the upregulation of TGF-β | In vitro, in vivo | [360] | |
| Acellular gelatinous Wharton's jelly of the human umbilical cord | Mechanism of action in skin wound healing. | Could be related to the paracrine effects of alpha-2-macroglobulin | In vitro, in vivo | [361] | |
| Human pluripotent stem cells | Photoaging by UVB irradiation and natural senescence | Decreases mRNA expression of MMP-1 and MMP-3 Increases the expression of type I collagen mRNA. |
In vitro | [362] | |
| Muscle | ASCs | Regeneration of skeletal muscle defect | Enhancing myocyte proliferation as well as MYOG and MYOD genes | In vitro, in vivo | [363] |
| Muscle regeneration | Increasing the number of centrally located nuclei | In vivo | [364] | ||
| C2C12 myoblasts | Promoting the musculoskeletal repair and regeneration | Exosomes derived from mechanically strained C2C12 cells improved cell proliferation and differentiation | In vitro | [365] | |
| Reveal the mechanism of interactions between exosomes and muscle regeneration | Increasing the levels of Pax7; an increase on day 3 and decrease on day 5 of peroxisome proliferator-activated receptor γ (PPARγ) levels, α-SMA, Collagen-1 | In vivo | [366] | ||
| Detecting endocrine signal role of exosomes | Regulating miRNAs, which are important for cell differentiation and growth control as well as myogenesis | In vitro | [367] | ||
| M2 macrophages | The role of exosomes derived from M2 macrophage on muscle regeneration | Exosomes enriched in miR-501, targeting Yin Yang 1, and increasing the levels of MyHC and MyoG | In vitro, in vivo | [368] | |
| PRPs and MSCs | Functional recovery of injured muscle | Increase in the expression of MYOG in PRP-exosome group; reduction of TGF-β in MSC-exosomes group; no effects on MYOD and IL-1β levels | In vivo | [369] | |
| MSCs | Muscle regeneration | Exosomes enriched in miR-21, miR-1, miR-133, miR-206, and miR-494 enhance tube formation and improve vascularization; increase myofibers diameter and centrally located nuclei; decrease fibrotic area; increase MYOD and MYOG expressions | In vitro, in vivo | [370] | |
| Human skeletal myoblasts, differentiating to myotube | Muscle regeneration | Enrich in growth factors such as IGFs, VEGF, HGF, NT-3, FGF2, and PDGF-AA; upregulation of FGF2, TNF, MYOD1, DAG1, DES, MYH1/2, and TNNT1 | In vitro and in vivo | [371] | |
| Liver |
Hepatocyte-derived cells | Promoting liver regeneration after acute liver failure | The miR-183-5p uptake leads to the activation of FoxO1/Akt/GSK3β/β-catenin signaling | In vitro, in vivo | [372] |
| Hepatocytes | Hepatocyte proliferation and regeneration after acute hepatic injury | Exosomal transfer of SK2 to target hepatocytes | In vitro, in vivo | [373] | |
| Human UCMSCs | Antioxidant and antiapoptotic effects, rescuing liver from failure | Might be correlated with GPX1 | In vivo | [374] | |
| Human BMSCs | Promote anti-fibrosis by stimulating hepatocyte regeneration | Suppression of Wnt/β-catenin signaling components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, Cyclin D1) | In vivo | [375] | |
| ASCs | Liver regeneration after hepatic ischemia-reperfusion in rats | Activation of Wnt/β-catenin signaling | In vivo | [376] | |
| Human Placenta-derived MSCs |
Upregulate angiogenesis and liver regeneration | Might be related with Wnt/β-catenin signaling triggered by C-reactive protein | In vitro, in vivo | [377] | |
| Promote cell proliferation and liver regeneration after hepatectomy |
Related with the exosomal circ-RBM23 mopping miR-139-5p, activating eIF4G expression and AKT/mTOR pathway |
In vitro, in vivo |
[378] |
||
| Vessel |
Endothelial progenitor cells | Reendothelialization | elevating angiogenesis genes levels such as HIF-1a, VEGF family, eNOS, E-selectin, IL8, ANG1, CXCL family; down-regulation of MMP-9 and PDFGB | In vitro, in vivo | [379] |
| Investigating the mechanism of vascularization by derived exosomes | Delivering miR-21-5p and targeting angiogenesis inhibitor Thrombospondin-1 | In vitro, in vivo | [380] | ||
| Induced vascular progenitor cells | angiogenesis | Enhance endothelial tube formation, cell migration, and proliferation; enrich in miR-143-3p, miR-291b, miR-20b-5p, and IGF-binding protein | In vitro, ex vivo, and in vivo | [381] | |
| MSCs cultured on titanium | Vascular regeneration | Improve VEGFR2 level and cell migration; downregulation of miR-15b-5p, miR-16-5p, miR-155-5p, miR-24-3p, miR-32-5p, mir-125b-5p, miR-146a-5p, and miR-320a | In vitro | [382] | |
| MSCs | Identifying the angiogenesis factors of exosomes | Induce proangiogenic via PDGF, EGF, FGF, and NFkB pathways | In vitro | [383] | |
| ASCs | Improving angiogenesis properties of EVs by PDGF | Enrich in proangiogenic factors such as MMP, c-kit, and SCF; enhance endothelial tube formation | In vitro, in vivo | [384] | |
| Annulus fibrous cells | Investigation of vascularization mechanism | Enhance endothelial cells migration and increase IL-6, TNF-α, MMP-3, MMP-13 and VEGF expressions | In vitro | [385] | |
| hypoxia-resistant multiple myeloma cell line | Improving angiogenesis | Upregulation of miR-210 and miR-135b, which miR-135b targets inhibiting hypoxia-inducible factor-1 | In vitro, in vivo | [386] | |
| Leukemia cells in hypoxia | Endothelial tube formation | Elevation of several miRNAs such as miR-18b and miR-210 | In vitro | [387] | |
| Lung cancer cells in hypoxia | Reveal the exosomal communication of cancer cells and endothelial cells | Elevation of miR-23a, suppression of t prolyl hydroxylase 1 and 2, increase in hypoxia-inducible factor-1α (HIF-1α) level, and downregulation of tight junction protein ZO-1 | In vitro, in vivo | [388] | |
| Overexpressed miR-21 ASCs |
The role of miR-21 on vascularization |
Increasing in HIF-1α, VEGF, SDF-1, p-Akt, p-ERK1/2 and decreasing in PTEN levels |
In vitro |
[389] |
|
| Cartilage | MSCs | Enhance proliferation, attenuate apoptosis, and modulate immune reactivity | Activation of AKT and ERK signaling, and higher infiltration of CD163+ M2 macrophages | In vitro, in vivo | [390] |
| Synovial MSCs | Enhance proliferation and migration in vitro and prevent osteoarthritis | Exosomal transfer of miRNA-140-5p to target cells. Might also be related with Wnt signaling | In vitro, in vivo | [391] | |
| Human BMSCs | Inhibit inflammatory mediators, promoting cartilage regeneration in vitro | Abolishment of TNF-alpha-mediated upregulation of COX2 | In vitro | [392] | |
| Subcutaneous MSCs | Ameliorate the pathological severity degree of cartilage | Delivery of miR-199a-3p-mediates mTOR-autophagy pathway | In vitro, in vivo | [393] | |
| KGN-pre-treated BMSCs | Chondral matrix formation and cartilage repair | Could be related to targeting C-myc and further regulating the MAPK signaling pathway | In vitro, in vivo | [394] | |
| Ovary | Amniotic fluid stem cells | POI | miR-369-3p inhibition of expression YAF2 and PDCD5/p53 in OGCs | In vitro, in vivo | [395] |
| POI | Anti-apoptosis and proliferative effect in OGCs by PI3K/AKT/mTOR pathway | In vitro, in vivo | [396] | ||
| POI | Anti-apoptosis on OGCs through regulation of miR-146a and miR-10a pathway | In vitro, in vivo | [397] | ||
| BMSCs | POI | Anti-apoptosis effect on OGCs through miR-144-5p suppressing PTE gene expression and this in turn increases PI3K/AKT pathway | In vitro, in vivo | [398] | |
| POI | Anti-apoptosis effect on OGCs through miR-664-5p inhibiting p53 luciferase activity | In vitro, in vivo | [399] | ||
| Amniotic fluid | POI | Antifibrotic effect by increasing SMAD6, which in turn inhibits the TGF-β signaling pathway | In vivo | [400] | |
| Ovarian tissue | POI | Anti-apoptosis effect in OGC by regulating BCL9 expression by miR-122-5p inhibitor | In vitro, in vivo | [401] | |
| Menstrual blood-derived stromal cells | POI and mechanism ovulation | Follicular development through increased A-azoospermia Like, proliferation of OGCs through increased forkhead box L2 | In vitro, in vivo | [402] | |
| Human UCMSCs | Inhibited apoptosis, increased OR, and recoopered the function of POI | Anti-apoptosis and proliferation effect in OGC through miR-17-5p inhibiting SIRT7 and target gene (γH2AX, PARP1 and XRCC6) | In vitro, in vivo | [403] | |
| Human ASCs | POI | Ovarian function is regulated through the SMAD pathway, which in turn inhibits the expression of apoptosis genes (Fas, FasL, caspase-3, and caspase-8) | In vitro, in vivo | [404] | |
| Skeleton | MSCs | osteogenesis | Improve the bone formation and expressions of angiogenesis genes such as VEGF, ANG 1, ANG2, COL1, and ALP | In vitro, in vivo | [405] |
| Fabricating cell-free scaffold for bone regeneration | Increasing the levels of osteogenic factors such as osteopontin, ALP, Hsa-miR-146a-5p, HsamiR-503-5p, Hsa-miR-483-3p, Hsa-miR-129-5p; decreasing the levels of anti-osteogenic miRNAs such as Hsa-miR-32-5p, Hsa-miR-133a-3p, and Hsa-miR-204-5p; activation of PI3K/Akt and MAPK signaling pathways | In vitro | [406] | ||
| Improving bone healing | Enrich in miR-4532, -125b-5p, −4516, -338-3p, and −548aa | In vitro, in vivo | [407] | ||
| BMSCs | Osteogenesis and bone tissue targeting | Enhancing the osteogenic activity of BMSCs due to elevation of miR-26a, −29a, −218, −34a, and −3960; enhancing bone localization of exosomes due to conjugation with BMSC-specific aptamer | In vitro, in vivo | [408] | |
| Promoting angiogenesis and regulating of osteoclast-related activities during bone remodeling process | miR-26a can influence bone formation through the Tob gene, which acts as a negative regulator of the BMP/SMAD pathway | In vitro, in vivo | [409] | ||
| human UCMSCs | Reduction of cell apoptosis | Elevation of miR-186, miR-1304, miR144, miR-1263, and miR-302b levels; regulation of apoptosis by inhibition Hippo signaling pathway | In vitro, in vivo | [410] | |
| Fracture healing | Elevation of β-catenin, Wnt3a, Col1, OPN, and RUNX2 | In vivo | [411] | ||
| ASCs | Osteogenesis effects of cell-free scaffold incorporated with exosomes | Improve cell migration, RUNX2, ALP, COL1A1 expressions of MSCs cultured in the osteogenic medium; enhance new bone formation | In vitro, in vivo | [412] | |
| Noggin-suppressed MSCs | Increasing bone healing efficacy | Downregulation of noggin; upregulation of ALP, RUNX2, Osterix, and OCN; inhibition of miR-26 | In vitro, in vivo | [413] | |
| miR‐375‐overexpressing ASCs | Improving bone regeneration with miR-375 | Exosomes were enriched in miR-375; improved osteogenesis of BMSCs, increase ALP, COL1A1, and RUNX2 levels as well as AZR quantification | In vitro, in vivo | [414] | |
| miR-21 transfected Human Wharton's jelly of UCMSCs | Decreasing osteocytes apoptosis | Elevation of miR-21-PTEN-AKT signaling pathway | In vitro, in vivo | [415] | |
| HIF-α overexpressing BMSCs | Improving bone healing with HIF-α | Increasing the levels of HIF-α, ALP, and OCN | In vitro, in vivo | [416] | |
| MSCs derived from human induced pluripotent stem cells | Improving osteogenesis and angiogenesis | Improving osteogenic differentiation and vascularization; Increase in ALP, RUNX-2, and COL1A1 levels | In vitro, in vivo | [417] | |
| MSCs derived from human induced pluripotent stem cells | Angiogenesis | Increasing microvessels and cell necrosis inhibition; upregulation of PI3K/Akt signaling pathway | In vitro, in vivo | [418] | |
| TNF-α preconditioned ASCs | Improving bone regeneration efficacy of exosomes | Upregulation of Wnt3a, RUNX2, osteopontin, and bone sialoprotein | In vitro | [419] | |
| Endothelial progenitor cells | Bone healing via angiogenesis | Enrich in miR-126; downregulation of SPRED1; regulation of Raf/ERK signaling pathway | In vitro, in vivo | [420] |
Abbreviations: Adipose-derived stem cells, ASCs; Bone marrow mesenchymal stem cells, BMSCs; Mesenchymal stem cells, MSCs; Umbilical cord mesenchymal stem cells, UCMSCs; Traumatic brain injury, TBI; Chemokine CC motif ligand 1, CCL1; Duchenne muscular dystrophy, DMD; Hyaluronidase 2, HAS2; Interleukin 10, IL-10; Heat shock proteins, HSP; heat shock factor 1, HSF1; Matrix metalloproteinase-1, MMP1; Matrix metalloproteinase-2, MMP2; Matrix metalloproteinase-3, MMP3; insulin-like growth factors, IGFs; vascular endothelial growth factor, VEGF; hepatocyte growth factor, HGF; neurotrophin-3, NT-3; fibroblast growth factor-2, FGF2; Platelet-derived growth factor-AA, PDGF-AA; Reactive oxygen species, ROS; Transforming growth factor beta, TGF-β; Tumor necrosis factor-alpha, TNF-α; Interleukin-6, IL-6; Bone morphogenetic proteins, BMP; Ultraviolet radiation, UV; Ultraviolet B, UVB; vascular endothelial growth factor, VEGF; microARN, miARN; ovarian granulosa cells, OGCs; Premature ovarian insufficiency, POI; Platelet-Rich Plasma, PRP; mother against decapentaplegic-related proteins, SMADs; SMAD family member 6, SMAD6.