From: Nrf2 activation: a key mechanism in stem cell exosomes-mediated therapies
Exosome cell source/species | Cargo and Loading mechanism | Exosome markers | Pathologies | Outcomes | Nrf2−/− or Nrf2 inhibitor | Refs. |
---|---|---|---|---|---|---|
BMSC/ SD rat | – | CD9, CD63, TSG101 | Diabetic wound | Exosomes improved the formation of EPC tubes, sped up the healing process, and reduced inflammation in diabetic wounds. By utilizing a Nrf2 activator, the therapeutic advantages of the exosomes were enhanced by Nrf2 activation | Nrf2 shRNA | [45] |
ADSC/SD rat | miR-130a-3p (transfection) | CD9, CD63, TSG101 | Diabetic peripheral neuropathy | miR-130a-3p delivery through ADSC-derived EVs activated Nrf2/HIF1α/ ACTA1 pathway by DNMT1 suppression to improve diabetic peripheral neuropathy through inhibiting schwann cells apoptosis | Nrf2 shRNA | [67] |
ADSC/ C57BL/KsJ db/m mice | – | CD9, CD63, CD81 | Diabetic nephropathy | Exosomes effectively alleviated inflammation and oxidative stress caused by high glucose in podocytes by upregulation of FAM129B and reactivation of the Nrf2-HO-1 pathway | HO-1 siRNA | [60] |
hUC-MSC/ Human | circHIPK3 (transfection) | CD63, CD81, TSG101 | Diabetes mellitus | circHIPK3 overexpressing exosomes provided a protective effect against cell injuries induced by high glucose and promoted angiogenesis in diabetic wounds by the direct inhibition of miR-20b-5p activity which leads to upregulation of Nrf2 and VEGFA expression | – | [74] |
BMSC | circ-ITCH (transfection) | CD63, CD9, TSG101 | Diabetic foot ulcers | Exosomal circ-ITCH blocked ferroptosis and stimulated the HUVECs angiogenesis by Nrf2 pathway activation through the recruitment of TAF15 protein and ultimately accelerated the healing process of wound | Nrf2 shRNA | [91] |
ADSC/ Human or rat | Nrf2 (transfection) | CD4, CD63, TSG101 | Diabetic foot ulcer | Exosomes extracted from Nrf2-overexpressing stem cells improved foot ulceration in diabetic rats | – | [87] |
BMSC/ C57BL/6 J mice | – | CD63, TSG101 | Respiratory distress syndrome | Exosomes mitigated sepsis-induced AECII apoptosis through restoring the mitochondrial dysfunction mediated by Nrf2 | ML385 Nrf2 inhibitor | [140] |
ADSC/ Human | miR-125b-5p | CD63, CD9, TSG101 | Sepsis lung injury | Delivery miR-125b-5p via exosomes reduced inflammation-induced ferroptosis in PMVECs and protected lung damage by regulation of Keap1/Nrf2/GPX4 axis | – | [133] |
hUC-MSC/ Human | miR-199a-5p (transfection) | HSP70, CD63, TSG101 | Acute lung injury | Exosomes enhanced the Nrf2 expression and translocation into the cell nucleus by transporting miR-199a-5p and interacting with CAV1 which led to upregulation of antioxidant enzymes expression within lung cells and regulation of oxidative stress | – | [134] |
hAMSC/ Human | Nrf2 (transfection) | CD9, CD63, CD81 | Acute lung injury | sEVs obtained from Nrf2-overexpressing hAMSCs protected against LPS -induced lung injury through preventing the NLRP3 activation and promoting the M2 macrophages polarization | Nrf2 siRNA | [126] |
BMSC/ C57BL/6 mice | circ_0072464 (transfection) | CD63, CD81, TSG101 | Intervertebral disc degeneration | circ_0072464 transported by EVs increased the levels of Nrf2 expression by competitive binding with miR-431 which led to ferroptosis suppression in nucleus pulposus cells and IDD alleviation | Nrf2 shRNA | [115] |
BMSC/Human | – | CD63, CD81 | Intervertebral disc degeneration | Exosomes restored the down-regulated antioxidant response system by modulation of the Keap1/ Nrf2 axis in degenerating nucleus pulposus cells | ML385 Nrf2 inhibitor, Nrf2 siRNA | [114] |
ADSC/SD rat | – | CD63, CD81, HSP-70 | Dexamethasone-induced bone loss | Exosomes reduced oxidative stress and apoptosis by regulation of Nrf2/HO-1 expressions and prevented the progression of glucocorticoid-induced osteoporosis | Nrf2 siRNA | [11] |
hUC-MSC/Human | – | TSG101, CD9, CD63 | Non-alcoholic steatohepatitis | Exosomes exerted anti-lipid deposition, anti-oxidative stress and anti-inflammatory effects through activation of Nrf2/NQO-1 pathway | ML385 Nrf2 inhibitor | [185] |
hUC-MSC/ Human | miR-24-3p (transfection) | CD9, CD63, CD81 | Nonalcoholic fatty liver disease | Delivery of miR-24-3p by exosomes effectively targeted Keap-1, leading to the inhibition of lipid synthesis and NF-kB signaling pathways, and improvement of Nrf2 activation in NAFLD | Keap1 siRNA | [179] |
BMSC/ C57BL/6 mice | Baicalin (transfection) | CD9, CD63, CD81, TSG101 | Acute liver injury | Exosomes derived from Baicalin-pretreated MSC exhibited a protective effect on liver function and activated the Keap1- Nrf2 pathway by P62, which prevents ROS generation and inhibits ferroptosis induced by lipid peroxides | ML385 Nrf2 inhibitor | [172] |
iPSCs–MSC/Human | – | – | Myocardial injury | Exosome led to promoted cardiomyocyte viability, improved cardiac function, reduced infarction ratio, and suppressed oxidation levels by activation Akt/Nrf2/HO-1 pathway | LY294002 PI3K/Akt inhibitor | [159] |
BMSC/ C57BL/6 mice | FNDC5 (transfection) | CD63, CD81, ALIX | Myocardial infarction | Exosomes derived from FNDC5-preconditioned BMSCs played a protective role against MI through anti-inflammatory effects and polarization of macrophage which partly reduced NF‐κB and upregulated Nrf2/ HO-1 Axis | SnPP HO-1 inhibitor | [46] |
BMSC/SD rat | Nrf2 (transfection) | CD63, CD81, CD9, TSG101, Alix | Atrial fibrillation | Lv-Nrf2 exosomes delivery suppressed arrhythmias induced by atrial fibrillation, myocardial apoptosis, fibrosis and inflammation by the Nrf2/HO-1 axis | – | [24] |
ADSC/ SD rat | – | CD9, CD63, HSP70 | MTX-induced neuronal damage | Exosomes inhibited oxidative stress triggered by MTX in hippocampus neurons by Nrf2-ARE activation | ML385 Nrf2 inhibitor | [196] |
BMSC/Mouse | – | CD63 | Delayed neurocognitive recovery (dNCR) | Exosome improved cognitive function by suppressing hippocampus ferroptosis through activation of the SIRT1/Nrf2/HO-1 axis in dNCR aged mice | EX-527 SIRT1 inhibitor | [197] |
hUC-MSC/Human | – | Flotillin-1, CD63, TSG101 | LPS/H2O2-induced neuroinflammation | Exosomes blocked the Nrf2/NF-κB p65/NLRP3 signaling pathway to attenuate oxidative stress and neuroinflammation, as well as increase a shift microglia phenotype from pro- to anti-inflammatory | ML385 NRF2 inhibitor | [237] |
ADSC/C57BL/6 mice | circAkap7 (transfection) | CD9, CD63, TSG101 | Cerebral ischemic injury | Exosome-circAkap7 provided protection against ischemic damage through enhancing ATG12-mediated autophagy and alleviated oxidative stress via increasing nuclear transcription of Nrf2 by absorbing miR-155-5p | Nrf2 siRNA | [194] |
BMSC/SD rat | miR-194 (transfection) | CD63, TSG101 | OGD/R | Exosomes loaded with miR-194 alleviated damage caused by OGD/R by suppressing expression of Bach1 and promoting the Nrf2/HO-1 axis activation via delivery of miR-194 to endothelial cells of brain vessels, which led to the ferroptosis reduction in these cells following hypoxic-ischemic brain injury | – | [193] |
hNSC/Human | – | CD9, CD63, CD81 | Hypoxia-reperfusion injury | Coculture of human NSCs-derived EVs with neurons inhibits the apoptosis of the neurons by inducing the translocation of NRF2 to neuronal nuclei, regulating the expression of oxidative stress-induced kinases | – | [195] |
BMSC/Wistar rat | miR-23b (transfection) | CD81, CD63, TSG101 | Intracerebral hemorrhage | Exosomal miR-23b ameliorated oxidative stress and neuroinflammation in ICH. PTEN acts as a target gene of miR- 23b by regulation of the Nrf2 signaling pathway and activation of NLRP3 inflammasome | – | [198] |
T-MSCs human | miR-100-5p | TSG101, CD9, HSP70 | Parkinson disease | Exosomes enriched with miR-100-5p provide a protective role against the degeneration of dopamine neurons and contribute to the preservation of the function of nigrostriatal system, improvement of motor impairments and mitigation of oxidative stress by modulating the Nox4-ROS-Nrf2 axis | ML385 Nrf2 inhibitor | [199] |
hUC-MSC/Human | – | CD63, CD81 | Oxidative stress-induced skin injury | Exosomes attenuated oxidative stress-induced skin damage by decreasing ROS production and improving the antioxidant capacities by the Nrf2 defense system regulation | ML385 Nrf2 inhibitor, Nrf2 siRNA | [191] |
ADSC/Rat | – | CD9, CD63, CD81 | Ultraviolet B-mediated Photoaging | Exosomes prevented ROS generation and DNA damage induced by UVB through activating the Nrf2 pathway and promoting protective antioxidants expression | – | [236] |
Placenta- MSC/Human | miR-21 (transfection) | CD63, CD9, HSP70 | Aging-related oxidative damage | Exosomes containing miR-21 upregulated the expression of the PTEN/PI3K-Nrf2 axis in senescent CD4 + T cells, improved their antioxidant capabilities, thereby attenuating age-related immunological dysfunction | PTEN inhibitor bpV (HOpic) | [214] |
hESC/Human | miR-200a | CD9, CD63, TSG-100 | Aged mouse skin pressure ulcer model | Exosomes accelerated wound healing and improved angiogenesis by rejuvenating endothelial senescence. In addition, they exerted the anti-aging impacts through the transfer of miR-200a to senescent endothelial cells and Nrf2 signaling activation | Brusatol Nrf2 inhibitor | [47] |
PDLSC/Human | miR-141-3p | CD9, CD63, CD81, TSG101 | High glucose induced senescence | Exosomes exhibited anti-aging effects by miR-141- 3p delivery to reduce KEAP1 expression and activate the Nrf2 antioxidant pathway | ML385 Nrf2 inhibitor | [30] |
Placenta- MSC/Human | miR-200a-3p | TSG101 ALIX, CD9, CD63 | AKI model induced by IRI | miRNA-200a-3p delivered by MSC-EVs activated the Keap1-Nrf2 pathway in TECs to exert antioxidant effects, which helps restore renal function by regulating mitochondrial structure and function | - | [225] |
hUC-MSC/Human | – | CD9, CD44, CD63, CD73 | AKI model induced by IRI | MSC-sEVs have the potential to alleviate AKI caused by I/R and can assist in balancing oxidative stress and antioxidative responses by enhancing the activation of Nrf2/ARE | – | [223] |
hUC-MSC/Human | ACE2 (transfection) | CD9, CD63, TSG101 | AKI model induced by IRI | MSC-ACE2-sEVs could protect the kidney against I/R injury, and this effect could be attributed to Nrf2/HO-1 axis activation | – | [226] |