Table 1.
Therapeutic potential of MSCs-EVs in inflammation disease
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Cell model/animal model
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Target cells in tissue
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Source of MSCs
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Cargo of MSCs-EVs
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Factors or pathways involved
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Therapeutic effects and mechanisms
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Ref.
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| ALI | ||||||
| Mouse BMDMs stimulated with LPS/C57BL/6 mouse with LPS-induced ALI | Alveolar macrophages | Human AT-MSCs | miR-27a-3p | NF-κB1 | In vitro: MSCs-EVs facilitated M2 polarization of BMDMs through the inhibition of NF-κB1 expression; in vivo: Systemic or intratracheal administration of MSCs-EVs reduced NF-κB1 expression in alveolar macrophages via miR-27a-3p delivery, promoting macrophage M2 polarization and alleviating LPS-induced ALI | [20] |
| Mouse MLE-12 cells (lung epithelial cells) barrier model/ICR mouse with sulfur mustard-induced ALI | Lung epithelial cells | Mouse BM-MSCs | Not detected | GPRC5A/YAP axis | In vitro: MSCs-EVs dose-dependently inhibited sulfur mustard-induced lung epithelial cell apoptosis and promoted the repair of adherens and tight junction integrity through the regulation of the GPRC5A/YAP axis, ultimately facilitating the recovery of epithelial barrier function; in vivo: Administration of MSCs-EVs protected lung epithelial cells from apoptosis and epithelial barrier damage by regulating the GPRC5A/YAP axis, promoting the restoration of barrier function and exerting a protective effect against pulmonary edema in ALI | [21] |
| HLMVECs injured by a mixture of IL-1β, TNF-α, and interferon-γ which were often used as a surrogate for ALI pulmonary edema fluid/- | - | Human BM-MSCs | Ang1 mRNA | Not detected | In vitro: MSCs-EVs partially increased Ang1 secretion in injured HLMVECs through the transfer of Ang1 mRNA, subsequently promoting the secretion of anti-permeability factors, restoring intercellular junctions, and preventing the formation of “actin stress fiber”, thereby dose-dependently restoring protein permeability across HLMVECs during ALI; in vivo: - | [22] |
| Sepsis | ||||||
| -/BALB/C mouse with LPS-induced sepsis | Not detected | Human UC-MSCs | Not detected | Not detected | In vitro: -; in vivo: Administration of MSCs-EVs effectively mitigated the destructive effects of inflammation caused by sepsis by reducing inflammatory factors, thereby alleviating tissue damage | [25] |
| -/C57BL/6 mouse with CLP-induced sepsis-induced ALI | Not detected | Human UC-MSCs | Not detected | MAPK/NF-κB pathway | In vitro: -; in vivo: MSCs-EVs can inhibit the phosphorylation and activation of the MAPK/NF-κB pathway, increase heme oxygenase 1 expression, enhance nuclear factor erythroid 2-related factor 2 expression, and upregulate antioxidant enzyme levels, thereby suppressing the infiltration of polymorphonuclear neutrophils to alleviate lung inflammation, improving pulmonary microvascular permeability to mitigate pulmonary edema, ultimately enhancing the survival rate of mice with sepsis-induced ALI | [26] |
| -/C57BL/6N mouse with CLP-induced sepsis-induced renal injury | Not detected | Hypoxia pretreated mouse AT-MSCs | mmu_circ_0001295 | Not detected | In vitro: -; in vivo: EVs secreted by hypoxia-pretreated MSCs can mitigate the elevated levels of plasma chemokines and cytokines induced by sepsis through the delivery of mmu_circ_0001295, thereby improving renal microvascular dysfunction, suppressing renal vascular leakage, and ultimately mitigating sepsis-induced renal dysfunction to enhance the survival rate of septic mice | [27] |
| Mouse RAW264.7 cells (monocytes/macrophages) stimulated with LPS/C57 mouse with LPS-induced sepsis | BMDMs | Mouse BM-MSCs | miR-17 | BRD4/EZH2/TRAIL axis | In vitro: MSCs-EVs suppressed the inflammation caused by RAW264.7 cells under LPS stimulation by delivering miR-17 to regulate the BRD4/EZH2/TRAIL axis; in vivo: MSCs-EVs, through the delivery of miR-17 to regulate the BRD4/EZH2/TRAIL axis, decreased serum levels of pro-inflammatory cytokines and suppressed their expression in BMDMs, ultimately improving LPS-induced sepsis in mice and enhancing survival rates | [28] |
| Mouse BMDMs stimulated with LPS/C57BL/6 mouse with CLP-induced sepsis | Liver macrophages | IL-1β pretreated mouse MSCs (source not mentioned) | miR-21 | PDCD4 | In vitro: MSCs-EVs induced M2-like polarization of macrophages, and IL-1β-pretreated MSCs-derived EVs exhibited an enhanced capacity to promote macrophage polarization towards an M2-like phenotype; in vivo: MSCs-EVs, by delivering miR-21, suppressed the effects of PDCD4 and induced M2-like polarization of macrophages, resulting in reduced inflammation, alleviated symptoms, prevented the progression of sepsis, and ultimately improved the survival rate | [29] |
| -/C57BL/6 mouse with CLP-induced sepsis-induced ALI or LPS-induced ALI | Alveolar macrophages | Mouse BM-MSCs | SAA1 | LPS | In vitro: -; in vivo: MSCs-EVs delivering SAA1 induced LPS internalization by mouse alveolar macrophages, leading to a decrease in inflammatory cytokine levels and ultimately alleviating sepsis-induced ALI | [30] |
| Mouse MH-S cells (alveolar macrophages) stimulated with LPS/C57BL/6 mouse with LPS-induced ARDS | Alveolar macrophages | Mouse BM-MSCs | Not detected | HIF-1α/glycolysis-related protein | In vitro: MSCs-EVs suppressed M1 polarization and promoted M2 polarization of alveolar macrophages by inhibiting cellular glycolysis, thereby exerting anti-inflammatory effects; in vivo: Intratracheal administration of MSCs-EVs attenuated the LPS-induced inflammatory response by suppressing glycolysis in alveolar macrophages via regulation of HIF-1α, leading to improved lung pathology, reduced lung edema, increased PaO2/FiO2 ratio, and therefore enhancing survival rate | [31] |
| Mouse RAW264.7 cells (monocytes/macrophages) or primary cardiomyocytes stimulated with LPS respectively/C57BL/6 mouse with LPS-induced sepsis-induced cardiac injury | Cardiomyocytes | Mouse BM-MSCs | miR-223, STAT3 and Sema3A proteins | STAT3, Sema3A | In vitro: MSCs-EVs suppressed the release of inflammatory cytokines in LPS-induced macrophages through the delivery of miR-223 and reduced LPS-induced cardiomyocyte apoptosis and cell death; in vivo: MSCs-EVs carrying miR-223 suppressed the expression of STAT3 and Sema3A, resulting in reduced serum levels of TNF-α, IL-1β, and IL-6, which in turn decreased cardiomyocyte apoptosis, improved cardiac function, and conferred cardio-protection in sepsis, ultimately reducing mortality. Additionally, by inhibiting miR-223 to pre-treat MSCs, the protein cargo within the secreted EVs can be reprogrammed, leading to an increased delivery of Sema3A and STAT3 proteins that exert detrimental effects on recipient cells | [33] |
| Rat H9c2 cells (cardiomyocytes) stimulated with LPS/C57BL/6 mouse with LPS-induced sepsis-induced cardiac injury | Myocardium | Rat BM-MSCs | miR-146a-5p | MYBL1 | In vitro: MSCs-EVs, by delivering miR-146a-5p, suppressed MYBL1 to inhibit the progression of LPS-induced cardiomyocyte inflammation, promoting cell proliferation, and inhibiting cell apoptosis; in vivo: MSCs-EVs administration can ameliorate cardiac injury and improve survival rates in septic mice | [34] |
| Human HL-1 cells (cardiomyocytes) model of cardiac dysfunction induced by LPS/C57BL/6 mouse with LPS-induced myocarditis | Cardiomyocytes | Mouse BM-MSCs | miR-223-3p | FOXO3/NLRP3 axis | In vitro: MSCs-EVs inhibited LPS-induced inflammation and pyroptosis in cardiomyocytes by delivering miR-223-3p, which targeted FOXO3 to suppress NLRP3 expression; in vivo: MSCs-EVs restricted myocardial tissue infiltration of inflammatory cells and inflammatory response, decreased cardiomyocyte pyroptosis, thus improving cardiac dysfunction by shuttling miR-223-3p, which targeted the FOXO3/NLRP3 axis | [35] |
| -/KM mouse with CLP-induced sepsis-induced cardiac injury | Cardiomyocytes | Mouse BM-MSCs | miR-141 | PTEN/β-catenin axis | In vitro: -; in vivo: MSCs-EVs ameliorated myocardial impairment and improved cardiac function by attenuating myocardial inflammatory infiltration and cell apoptosis in septic mouse myocardial tissues through the delivery of miR-141 and regulation of the PTEN/β-catenin axis | [36] |
| RAT H9c2 cells or human AC16 cells (cardiomyocytes) stimulated with LPS respectively/wistar rat with CLP-induced sepsis-induced cardiac injury | Cardiomyocytes | Human MSCs (source not mentioned) | circRTN4 | miR-497-5p/MG53 axis | In vitro: MSCs-derived exosomal circRTN4 improved cell survival and suppressed apoptosis in LPS-stimulated cardiomyocytes by targeting the miR-497-5p/MG53 axis; in vivo: MSCs-EVs, administered through injection into three different sites around renal tissue for three consecutive days after CLP, delivered circRTN4 to suppress oxidative stress, reduce inflammation factors, and alleviate apoptosis, resulting in the mitigation of cardiac injury | [37] |
| Human AC16 cells (cardiomyocytes) stimulated with LPS/C57BL/6 mouse with CLP-induced sepsis-induced cardiac injury | Cardiomyocytes | Human UC-MSCs | PINK1 mRNA | PKA/NCLX axis | In vitro: MSCs-EVs mediated the delivery of PINK1 mRNA to regulate cardiomyocyte mCa2+ efflux through the PKA/NCLX axis; in vivo: MSCs-EVs mediated the transfer of PINK1 mRNA, leading to the maintenance of normal mCa2+ efflux, alleviation of mitochondrial calcium overload, and subsequent mitigation of cardiomyocyte injury caused by mitochondrial damage, resulting in improved cardiac function and increased survival rate | [38] |
| AP | ||||||
| -/SD rat with impactor-induced traumatic AP | Pancreatic tissue | Human UC-MSCs | Not detected | Not detected | In vitro: -; in vivo: MSCs-EVs inhibited the apoptosis of pancreatic acinar cells, controlled the systemic inflammatory response, and thereby attenuated pancreatic tissue injury and facilitated the repair of pancreatic tissue | [39,40] |
| Mouse MPC-83 cells (pancreatic acinar cells) stimulated with caerulein/C57BL/6J mouse with caerulein-induced AP | Pancreatic acinar cells | Mouse HF-MSCs | Not detected | Pyroptosis-related protein | In vitro: MSCs-EVs enhanced cell viability, mitigated inflammation, and attenuated the expression of pyroptosis-related proteins in caerulein-stimulated pancreatic acinar cells; in vivo: Intraperitoneal or intravenous administration, especially intravenous injection, of MSCs-EVs, can mitigate pancreatic acinar cell pyroptosis, alleviate the inflammatory response and oxidative stress in AP, thus reducing the severity of pancreatic injury | [41] |
| Cardiovascular diseases | ||||||
| Mouse HL-1 cells (cardiomyocytes) hypoxia model/C57BL/6J mouse with LAD ligation-induced AMI | Cardiomyocytes | Mouse BM-MSCs | miR-302d-3p | BCL6/MD2/NF-κB axis | In vitro: MSCs-EVs carrying miR-302d-3p improved the viability of hypoxic cardiomyocytes, suppressed inflammation, and inhibited apoptosis by targeting the BCL6/MD2/NF-κB axis; in vivo: Intramyocardial injection of MSCs-EVs carrying miR-302d-3p near the infarcted area attenuated cardiomyocyte apoptosis and cardiac inflammation by targeting the BCL6/MD2/NF-κB axis, leading to reduced infarct size and myocardial fibrosis, thereby suppressing post-AMI cardiac remodeling and improving cardiac dysfunction | [42] |
| Mouse RAW264.7 cells (monocytes/macrophages) stimulated with LPS/C57BL/6J mouse with LAD ligation-induced ischemia-reperfusion injury | Cardiac macrophages | Mouse BM-MSCs | miR-182 | TLR4/NF-κB/PI3K/Akt signalling cascades | In vitro: MSCs-EVs carrying miR-182 facilitated the polarization of macrophages from an M1 to M2 phenotype in an inflammatory environment by inhibiting the TLR4/NF-κB signaling pathway and activating the PI3K/Akt signaling pathway through cross-talk between them; in vivo: MSCs-EVs carrying miR-182 regulated myocardial inflammation and reduced infarct size, thereby attenuating myocardial ischemia-reperfusion injury and improving cardiac function in mice through the promotion of macrophage M2 polarization via targeting the TLR4/NF-κB/PI3K/Akt signaling cascades | [43] |
MSCs: Mesenchymal stem cells; EVs: Extracellular vesicles; BM-MSCs: Bone marrow-derived MSCs; AT-MSCs: Adipose tissue-derived MSCs; UC-MSCs: Umbilical cord-derived MSCs; HF-MSCs: Hair follicle-derived MSCs; Akt: Protein kinase B; ALI: Acute lung injury; AMI: Acute myocardial infarction; Ang1: Angiopoietin-1; AP: Acute pancreatitis; BCL6: B-cell leukemia/lymphoma 6; BMDMs: Bone marrow-derived macrophages; BRD4: Bromodomain-containing protein 4; CLP: Cecal ligation and puncture; EZH2: Enhancer of zeste homolog 2; FOXO3: Forkhead box protein O3; GPRC5A: G protein-coupled receptor family C group 5 member A; HIF-1α: Hypoxia-inducible factor-1α; HLMVECs: Human lung microvascular endothelial cells; IL-1β: Interleukin-1β; LAD: Left anterior descending coronary artery; LPS: Lipopolysaccharide; MAPK: Mitogen-activated protein kinase; MD2: Myeloid differentiation protein 2; MG53: Mitsugumin 53; MYBL1: Myb-like protein 1; NCLX: Mitochondrial Na+/Ca2+ exchanger; NF-κB: Nuclear factor-κB; NF-κB1: Nuclear factor-κB subunit 1; NLRP3: NOD-like receptor thermal protein domain associated protein 3; PDCD4: Programmed cell death 4; PI3K: Phosphatidylinositol 3-kinases; PINK1: PTEN-induced putative kinase 1; PKA: Protein kinase A; PTEN: Phosphatase and tensin homolog deleted on chromosome 10; SAA1: Serum amyloid A1; Sema3A: Semaphorin 3A; STAT3: Signal transducers and activators of transcription 3; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; YAP: Yes-associated protein.