Table 2.
Comparisons of extracellular vesicles (EVs) treatment from various mesenchymal stem cells and their clinical relevance to liver injury and disease.
| Extracellular Vesicles | Cell Source | Molecular Mediators in the EVs Cargos | Recipient Targets Model | Interaction | Clinical Relevance | Reference |
|---|---|---|---|---|---|---|
| Exosomes | Human umbilical cord MSCs (hucMSC) | mRNA, surface adhesion molecules | Acute liver injury mice model (CCl4 treatment) | hucMSC exosomes recovered AST activity, reduced COL1A1, COL3A1, and TGF-β1 expressions | Alleviation of liver fibrosis | [73] |
| Exosomes | hucMSC | GPX1 | Acute liver injury mice model (CCl4 treatment) | Reduction of hepatic ROS and apoptosis by increasing the ERK1/2 and BCL-2 and decreasing the IKKB/NFkB/Casp-9/-3 pathway | The recovery of hepatic oxidant injury | [81] |
| Exosomes | hucMSC | - | Acute liver injury mice model (LPS and D-galactosamine treatment), RAW264.7 macrophages | Reduction of NLRP3, Casp-1, IL-1β, IL-6 expressions in the macrophage, liver ALT and AST levels, and the restoration of damaged liver tissue | Reduced inflammation and liver damage is repaired | [83] |
| Exosome | Chorionic plate-derived MSCs (CP-MSCs) | miR-125b | Acute liver injury mice model (CCl4 treatment), hepatic stellate cells (HSCs) | miR-125b suppressed the activation of Hh signaling that promotes fibrosis | Suppression of the HSCs activation and proliferation | [92] |
| Exosomes | MSCs | - | Acute liver injury mice model (CCl4 treatment), hepatocytes | MSCs exosomes activated proliferation genes and prevented apoptosis | MSC-derived exosomes have hepatoprotective effects against acute-liver injury | [74] |
| Exosomes | Adipose tissue-derived MSCs (AMSCs) | miR-17 | Acute liver injury mice model (LPS and D-galactosamine treatment), Kupffer cells | miR-17 reduced TXNIP expression and suppressed the NLRP3 inflammasome activation in Kupffer cells | Reduction of inflammatory activation in Kupffer cells | [89] |
| Exosomes | AMSCs | miR-181-5p | Acute liver injury mice model (CCl4 treatment), HSCs | miR-181-5p increased autophagy and reduced liver fibrosis by inhibiting the STAT3/BCL-2/Beclin-1 pathway HSCs COL1A1, VIMENTIN, α-SMA, and FN1 expressions were reduced | AMSCs exosomal miR-181-5p has an anti-fibrotic role | [93] |
| Exosomes | AMSCs | miR-122 | Acute liver injury mice model (CCl4 treatment), HSCs | miR-122 reduced the expression of IGF1R, CCNG1, and P4HA1 in HSCs | Suppression of the HSCs proliferation and collagen maturation | [94] |
| Exosome | Adipose-derived stem cells (ADSC) | STAT3 | Mice fed high-fat diets, macrophages | ADSC exosomes improved insulin sensitivity, reduced obesity, and alleviated hepatic steatosis, by inducing the anti-inflammatory phenotypes in M2 macrophages via the transactivation of arginase-1 by exosome-STAT3 | Improvement of insulin regulation and hepatic steatosis | [72] |
| Exosomes | Bone-marrow-derived MSC (BMSCs) | - | Acute liver injury mice model (CCl4 treatment), hepatocytes (Acetaminophen or hydrogen peroxide treatment) | Reduced ROS production and prevented oxidative stress, as well as improved liver regeneration and recovery | The recovery of hepatic oxidant injury | [76] |
| Exosomes | BMSCs | - | Hepatocytes (LPS and D-galactosamine treatment) | BMSCs exosomes reduced the pro-apoptotic proteins BAX, and cleaved Casp-3, and increased the expression of the anti-apoptotic BCL-2 | Induce autophagy and protect hepatic cells from damage caused by various stresses by mediating autophagy | [80] |
| Exosome | BMSCs | - | Acute liver injury mice model (CCl4 treatment), HSCs | BMSCs exosomes alleviated liver fibrosis and inflammation, as well as reduced the expression of Wnt/β-catenin pathway components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, CCND1, α-SMA, and COL1A1) in HSCs and liver tissue | Alleviation of liver fibrosis via the inhibition of Wnt/β-catenin signaling | [79] |
| Exosomes | Human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) |
- | Liver injury mice model (ischemia/reperfusion surgery), hepatocytes | hiPSC-MSCs exosomes reduced AST and ALT levels and increased primary hepatocyte proliferation and synthesis of S1P | Protection against hepatic ischemia/reperfusion injury | [86] |
| Exosomes | Human menstrual blood-derived stem cells (MenSCs) | ICAM-1, angiopoietin-2, Axl, angiogenin, IGFBP-6, osteoprotegerin, IL-6, and IL-8 | Acute liver injury mice model (LPS and D-galactosamine treatment), AML12 macrophage cells | MenSCs exosomes improved liver function and inhibited apoptosis with a reduction of active Casp-3 | Inhibition of cell apoptosis and enhanced survival | [87] |
| Microvesicles (MVs) | Human liver stem cells (HLSC) | mRNAs | Hepatocytes | HLSC MVs activated cell proliferation and liver regeneration | Liver regeneration | [84] |
| Extracellular vesicles | HLSC | ASS1 protein and mRNA | Hepatocytes derived from ASS1 deficient HLSC | HLSC EVs restored ASS1 activity and urea production | Restoration of ASS1 function in deficient cells | [85] |
| Extracellular vesicles | HLSC | NASH mice model (choline-deficient amino acid diet) | HLSC EVs reduced fibrosis and inflammation markers (α-SMA), COL1A1, TGF-β1, TNF-α, IL-1β, and LTBP1 | Reduction of inflammation and fibrogenesis | [98] | |
| Extracellular vesicles | hucMSC | MnSOD enzyme | Liver injury mice model (ischemia/reperfusion surgery) | hucMSC EVs reduced neutrophils infiltration and alleviated hepatic oxidative stress | Inhibition of the oxidative stress and neutrophil inflammatory response | [82] |
| Extracellular vesicles | hucMSC | - | Liver injury mice model (S. japonicum infection), HSCs | hUCMSC EVs ameliorated liver injury and reduced the expression of α-SMA, COL1A1, and COL3A1, as well as HSCs proliferation | Suppression of HSCs proliferation and improved liver condition | [99] |
| Extracellular vesicles | Amnion-derived mesenchymal stem | - | NASH mice model (high-fat diets), Acute liver injury mice model (CCl4 treatment), HSCs and Kupffer cells | AMSC EVs reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and TGF-β), fibrosis, Kupffer cell numbers, and HSC activation | Reduction of inflammation and fibrogenesis | [97] |
| Extracellular vesicles | BMSCs | Y-RNA-1 | Liver failure mice model (D-galactosamine/TNF-α treatment), hepatocytes | BMSCs EVs reduced hepatic injury and apoptosis | Protective effect against hepatocyte apoptosis | [75] |
| Extracellular vesicles | BMSCs | - | Liver injury mice model (ischemia/reperfusion surgery), hepatocytes | BMSCs EVs reduced tissue necrosis, apoptosis, serum ALT, and increased expression of NLRP12 and CXCL1, as well as increased the expression of IL-6 | Reduction of tissue necrosis, inflammation, and apoptosis | [77] |
| Extracellular vesicles | Human mesenchymal stromal cell (hMSCs) | - | Liver injury mice model (ischemia/reperfusion surgery) | hMSCs EVs reduced hepatic necrosis and inflammatory genes (HMBG-1, ICAM-1, HO-1, and IL-1β) | Reduction of tissue necrosis and inflammation | [78] |
| Extracellular vesicles | Human embryonic stem cell-derived mesenchymal stroma cells | - | Liver injury mice model (thioacetamide treatment) | EVs reduced fibrosis, apoptosis, and regenerated liver cells | Regeneration of liver | [64] |
| Extracellular vesicles | Human adipose-derived stem cells (hASCs) | lncRNA H19 | Acute liver injury mice model (D-galactosamine treatment) | hASCs EVs reduced the expression of inflammatory mediators and chemotactic factors | Inhibition of the liver inflammation | [90] |
| Extracellular vesicles | hASCs | - | NASH mice model (high-fat diets) with acute liver injury (LPS treatment) | hASCs EVs reduced serum ALT levels and inflammatory markers and macrophages | Inhibition of the liver inflammation | [95] |
| Extracellular vesicles | Human induced pluripotent stem cell (iPSCs) | MicroRNAs (specifically miR-92a-3p) | HSCs | iPSCs EVs reduced pro-fibrogenic markers (α–SMA, COL1A1, FN1, and TIMP-1), and HSC proliferation | Inhibition of fibrosis and HSCs proliferation | [96] |
Abbreviations: Adipose tissue-derived MSCs: (AMSCs), Alanine aminotransferase (ALT), Alpha-smooth muscle actin (α-SMA), Argininosuccinate synthase-1 (ASS1), Aspartate aminotransferase (AST), B-cell lymphoma 2 (BCL-2), BCL-2 Associated X-protein (BAX), Bone-marrow-derived MSCs (BMSCs), C-X-C motif chemokine ligand 1 (CXCL1), Carbon tetrachloride (CCl4), Caspase (Casp), Chorionic plate-derived MSCs (CP-MSCs), Collagen type I (COL1A1), Collagen type III (COL3A1), Cyclin D(1) (CCND1), Cyclin G(1) (CCNG1), Extracellular signal-regulated kinases 1/2 (ERK1/2), Extracellular vesicles (EVs), Fibronectin (FN1), Glutathione peroxidase1 (GPX1), Hedgehog (Hh), Hepatic stellate cells (HSCs), Heme oxygenase-1 (HO-1), High mobility group box 1 protein (HMBG-1), Human adipose-derived stem cells (hASCs), Human-induced pluripotent stem cell–derived mesenchymal stromal cells (hiPSC-MSCs), Human induced pluripotent stem cell (iPSCs), Human liver stem cells (HLSC), Human menstrual blood-derived stem cells (MenSCs), Human umbilical cord MSCs (hucMSC), IκB kinase (IKKB), Insulin-like growth factor-binding protein 6 (IGFBP-6), Insulin-like growth factor receptor 1 (IGF1R), Intercellular adhesion molecule 1 (ICAM-1), Interleukin-1 β (IL-1 β), Interleukin-6 (IL-6),), Interleukin-8 (IL-8), Latent-transforming growth factor beta-binding protein 1 (LTBP1). Lipopolysaccharides (LPS), Mesenchymal stem cells (MSCs), Messenger RNA (mRNA), Microvesicles (MVs), Mitochondria-located antioxidant enzyme, manganese superoxide dismutase (MnSOD), NLR family pyrin domain containing 3 (NLRP3), NLR family pyrin domain containing 12 (NLRP12), Nonalcoholic steatohepatitis (NASH), Noncoding RNA Y (Y-RNA-1), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFkB), Reactive oxygen species (ROS), Peroxisome proliferator-activated receptor gamma (PPARγ), Prolyl-4-hydroxylase α1 (P4HA1), Signal transducer and activator of transcription 3 (STAT3), Sphingosine-1-phosphate (S1P), Thioredoxin Interacting Protein (TXNIP), Tissue inhibitor of metalloproteinases–1 (TIMP-1), Transforming growth factor beta-1 (TGF-β1), Tumor necrosis factor-alpha (TNF-α), Wingless and Int-1 (Wnt), Wnt1-inducible signaling pathway protein-1 (WISP1).