Table 1.
Studies testing the immunomodulatory effects of MSCs/MSC-sEVs on liver disease.
| Diseases | Origin of MSCs/MSC-sEVs | Species | Dose | Application | Ref | |
|---|---|---|---|---|---|---|
| ALF | HucMSC-sEVs | Male C57BL/6 | — | Overexpression of miR-455-3p attenuates MΦ infiltration and local liver damage and reduces the serum levels of inflammatory factors | (12) | |
| HADSCs | Balb/c mice | 4 × 105 via tail vein | Lipid-conjugated heparin coat results in enhanced delivery, longer retention, faster decrease in AST and ALT, and alleviated inflammatory response | (13) | ||
| HucMSCs | Balb/c mice | 5 × 105 via tail vein | Engrafts in the injured liver and repairs damaged tissue | (14) | ||
| HucMSCs | Male mice | 1 × 106 intravenously | Inhibits inflammatory cytokine and chemokine levels and reduces immune cell infiltration into the liver tissue, also attenuates hepatocyte apoptosis | (15) | ||
| Rat BMSCs | Male SD rats | 1 × 107/kg via tail vein | IL-1β-pretreatment enhances efficacy on survival rate, liver function, and liver necrosis suppression with more MSCs migrated to the damaged liver | (16) | ||
| HucbMSCs | Male SD rats | 1 × 107 in via tail vein | VEGF165 overexpression enhances the multipotency of MSCs in stronger effectiveness, homing, and colonization | (17) | ||
| BMSCs | SD rats | 2.4 ml of CM for 3 consecutive days | Has higher cell viability and total protein synthesis in vitro, prevents the release of liver injury biomarkers, and promotes the recovery of the liver structure in vivo | (18) | ||
| BMSCs | Male C57BL/6J | 2 × 106 via tail vein | MSC-derived PGE2 inhibits inflammatory activation of MΦ, promotes inflammatory resolution, and limits injury | (19) | ||
| EMSCs | Syngeneic male SD rats | CM of 5 × 106 inject intraperitoneally | Magnetic graphene oxide enhances the effect on reducing necrosis, inflammation, AST, ALT, and ALP, as well as the VEGF and MMP-9 | (20, 21) | ||
| Hepatitis B | HBMSCs | Balb/c mice | 1 × 106 via tail vein | Influences innate immunity and limits immune-mediated liver injury by suppressing NK-cell activity | (22) | |
| HBMSCs | Human | 1–10 × 105/kg once a week for 4 weeks | Significantly increases the 24-week survival rate by improving liver function and decreasing the incidence of severe infections safely and conveniently | (23) | ||
| HucMSCs | Human | 1 × 108 via infusion pump | Further improves the hepatic function and survival | (24) | ||
| HucMSCs | Human | 105/kg intravenously | No significant advance in the short-term prognosis with further evaluated needed in the long-term efficacy | (25) | ||
| Hepatitis C | Mice BMSCs | H-2d mice | 5 × 105 via tail vein | Exhibits promising adjuvant property | (26) | |
| Autologous hBMSCs | Human | Fasting for intravenous infusion 1 × 106/kg | Supportive in the treatment of end-stage liver disease, with satisfactory tolerability and beneficial effects on liver synthetic functions and hepatic fibrosis. | (27) | ||
| Mice BMSCs | H-2d mice | 5 × 105 via tail vein | Enhances immune response | (28) | ||
| NASH | HucMSCs | C57BL/6 mice | 200 ml CM/3 days for 2 months | Improves insulin resistance, amends pathological structure, enhances total antioxidant capacity and mitochondrial function, and reduces inflammation and apoptosis | (29) | |
| HADSCs | C57BL/6J mice | — | Reduces systemic inflammation and fat accumulation in the liver, increases browning of white adipose tissue depots, and improves glucose tolerance | (30) | ||
| HADSCs and HADSC-sEVs | Mc4r-KO C57BL/6J mice | 1 × 106 cells; 1.0, 2.5, or 5.0 mg | Decreases serum ALT levels and inflammatory markers, improves fibrosis, and increases anti-inflammatory MΦ | (31) | ||
| Rat BMSCs | Male SD rats | 2 × 106 via tail vein | Ameliorates liver lipotoxicity and metabolic disturbance | (32) | ||
| AIH | Mouse ADSCs | C57BL/6J mice | — | IL-35 gene modification manages MSCs to better migrate to injured liver tissues, narrows the necrosis areas of injured livers, and prevents the hepatocyte apoptosis | (33) | |
| BMSC-sEVs | C57BL/6 mice | 2 µg/g | Attenuates inflammatory responses and inflammatory cytokine release in both the liver and MΦ | (34) | ||
| BMSC-sEVs | Wild-type male C57BL/6 mice | 20 μg/ml | Reverses injury in mice and hepatocytes, and downregulates the expressions of cytokines, NLRP3, and caspase-1 | (35) | ||
| Liver fibrosis | ADSCs | C57BL/6 mice | 400 μl CM | Decreases hepatic enzymes and collagen deposition | (36) | |
| Mice BMSCs | C57BL/6 mice | 1 × 106 | Erythropoietin-overexpressed MSCs significantly alleviate liver fibrosis | (37) | ||
| HucMSCs | C57BL/6 mice | 5 × 105 via tail vein | Ameliorates liver fibrosis, attenuates collagen deposition, and improves liver function | (38) | ||
| ADSC-sEVs | C57BL/6J mice | 0.4 μg/μl, 100 μl | Inhibits collagen volume fraction and reduces inflammatory factor levels and hepatic injury-associated indicators. | (39) | ||
| HBMSC-sEVs | SD rats | 250 mg | Alleviates liver fibrosis with a reduction in collagen accumulation, enhancement in liver functionality, inhibition of inflammation, and raise in hepatocyte regeneration | (40) | ||
| Rat BMSCs | Albino rats | 3 × 106 | Reverses the deterioration of liver function | (41) | ||
| HTMSC-sEVs | C57BL/6 mice | 150 mg/mouse | Attenuates HSC activation and liver fibrosis through miR-486 in sEVs | (42) | ||
| Liver cirrhosis | HBMSCs and hADSCs | C57BL/6 mice | 1 × 106 | Attenuates liver damage, improves liver function, and regresses liver fibrosis | (43) | |
| HucMSCs | Human | 3 times of 0.5× 106/kg at 4-week intervals | Markedly improves liver function with a significant higher overall survival rate | (44) | ||
| Rat BMSCs | Wistar rats | 3–5 × 106 via surgical incision | Mitigates liver cirrhosis | (45) | ||
| Autologous hBMSCs | Human | 5 × 107 once/twice | Safely improves histologic fibrosis and liver function in patients with alcoholic cirrhosis | (46) | ||
| Liver GvHD | HucMSCs | Human | 1 × 106/kg body weight | Decreases ALT level and remains lower; increases Treg/Th17; increases transforming growth factor β1 and prostaglandin E2 | (47) | |
| HBMSCs | Human | 1.5–3 × 106/kg on postoperative day 3 | Long-term results of feasibility, safety, and tolerability of MSC infusion | (48) | ||
| HBMSCs | Human | 1–2 × 106/kg | Induces mild positive changes in immunoregulatory T and NK cells | (49) | ||
| HucMSCs | Human | 1 × 106/kg | Decreases the need for interventional therapies and improves the graft survival rates | (50) | ||
| HucMSCs | Human | 1 × 106/kg | Decreases the incidence of acute rejection, rates of biliary complications, and infection | (51) | ||
| HCC | Rat BMSCs | Rat | 1 × 106/ml PBS | Melatonin pretreatment yields MSCs a better ameliorative effect | (52) | |
| HBMSC-sEVs | Nude mice | — | Reduces proliferation, migration, invasion, and self-renewal abilities of HCC cell lines | (53) | ||
| HBMSCs | Nude mice | Intravenously inject 1 × 106 cells at days 9 and 13 | Modification of the virus’ fiber domain in MSCs results in a high level of virion accumulation in HCC and potent tumor growth inhibition | (54) | ||
| HAMSC-sEVs | Male Balb/c nude mice | 10 mg/kg once per week | miR-199a-modified MSCs effectively deliver miR-199ay to HCC, inhibit the mTOR pathway, and improve HCC chemotherapy | (55) | ||
| HucMSCs | Male Balb/c nude mice | A mixture of hepatoma cells and MSCs equally | Inhibits the growth of liver cancer cells | (56) | ||
| HBMSCs | Female CD1 nu/nu mice | 0.5 × 106 CMV-NIS-MSCs | MSCs show temperature-dependent migration | (57) | ||
| HPMSCs | Male athymic nude mice | 5 × 105 via tail veins or into the tumor margin | MSCs combined with chemotherapy yields favorably result with higher tumor necrosis and greater proportion of apoptotic-positive cells | (58) | ||
| HBMSC-sEVs | Balb/c mice | 2 mg/kg | Delivery of anticancer drug norcantharidin induces cell-cycle arrest, reduces tumor cell proliferation, increases apoptosis, and exerts obvious in vivo antitumor effects | (59) | ||
MSCs, mesenchymal stem cells; sEVs, small extracellular vesicles; HucMSCs, human umbilical cord-derived MSCs; ADSCs, adipose-derived MSCs; BMSCs, bone marrow-derived MSCs; PMSCs, placenta-derived MSCs; HTMSCs, human tonsil-derived MSCs; AMSCs, amnion-derived MSCs; HucbMSCs, human umbilical cord blood-derived MSCs; EMSCs, embryonic stem cell-derived MSCs; CM, conditioned medium; ALF, acute liver failure; AH, alcoholic hepatitis; NASH, non-alcoholic steatohepatitis; AIH, autoimmune hepatitis; HSC, hepatic stellate cells; GvHD, Graft versus host diseases; HCC, hepatocellular carcinoma; SD, Sprague-Dawley; Mc4r-KO, melanocortin type-4 receptor knockout; H-2d mice, mice of the DBA/2J (H-2d) line; alga-PEG, alginate-polyethylene glycol; CMV, Cytomegalovirus; NIS, theragnostic sodium iodide symporter.