TABLE 1.
Anti-fibrotic effect of MSCs from different sources in chronic liver injury.
| Type of cells | Source | Liver fibrosis model | Mechanism of action | References |
| Murine MSCs | BM mononuclear cell fraction selected by plastic adherence | Intraperitoneal (i.p.) administration of a 1.0 ml/kg dose of CCl4 twice a week for 4 weeks | Reduction of collagen deposition by downregulating α-SMA and TIMP-1 gene expression | Rabani et al., 2010 |
| Murine hepatocyte-differentiated BM-MSCs (in the presence of HGF, FGF4, and EGF) | Tibia and femur of Sprague–Dawley (SD) rats | 0.5 ml/kg CCl4 was injected subcutaneously into adult male SD rats (320 ± 20 g) twice a week for 4 weeks | Improvement of liver function by modulating the gene of ECM remodeling (MMP-2, MMP-9, and TIMP-1), reducing the expression of IL-1β, IL-6, TNFα, and TGF-β, and increasing IL-10 and HGF | Zhao et al., 2012 |
| Human BM-MSCs and human MSCs | Purchased from Lonza | CCl4 dissolved in corn oil (1:3) twice a week for 6 weeks for the last 4 weeks | Fibrosis reduction by improvement of MMP-9, which degrades the ECM, and downregulation of αSMA, TNFα, and TGF-β, markers of activated HSCs | Tanimoto et al., 2013 |
| Murine MSCs and hepatocytes | Tibia and femur of 2-month-old C57BL/6 mice | In vitro: hepatocytes were seeded on a 6-well collagen-coated plate (1 × 104 cells/cm2) and were subjected to injury with 3 mM and 5 mM CCl4. In vivo: female C57BL/6 mice (6–8 weeks old) intraperitoneally injected with 1 ml/kg CCl4 in olive oil (1:1) for 4 weeks. | In vitro: reduction of apoptotic markers, such as Bax, caspase-3, NF-κB, IL-6, and TNF-α, and increased levels of anti-apoptotic marker Bcl-xl. In vivo: increased expression of Bcl-xl and reduction of expression levels of apoptotic markers Bax, caspase-3, NF-κB, and TNF-α | Nasir et al., 2013 |
| Human BM-MSCs | Posterior iliac crest of healthy donors | i.p. injections of TAA (300 mg/kg body weight) twice a week for 12 weeks in SD rats | Recovery from TAA induced fibrosis by decreasing TGF-β1, type I collagen, and α-SMA expression and modulating the TGF-β1/SMAD signaling pathway | Jang et al., 2014 |
| Human hepatocyte-differentiated BM-MSCs | Knee or hip joint of human donors | Immunodeficient male Pfp/Rag2–/– mice that underwent 1/3 partial hepatectomy after 42 days of MCDD | Presence of human hepatocyte-like cells in the mouse liver parenchyma attenuating inflammation markers (TNFα). Reduction of the expression of α-SMA and type I collagen mRNA | Winkler et al., 2014 |
| Human BM-MSCs | BM of human healthy donors | In vitro model: co-culture of BM-MSCs with HSCs in transwell condition for 24, 48, and 72 h | Inhibitory effect of BM-MSCs on HSC proliferation and induction of the apoptosis through the inhibition of the TGF-β1/SMAD pathway in HSCs | Zhang et al., 2015 |
| Murine BM-MSCs | Femur of healthy Swiss mice | Male Swiss mice treated by 1.0 ml/kg CCl4 via oral administration 3 times/week (every 2 days) for 11 weeks | Inhibition of fibrogenesis with the reduction of integrin, TGF-β1, and pro-collagen expression | Truong et al., 2016 |
| Adult human BM-MSCs and neonatal human Wharton’s jelly (WJ)-MSCs | BM mononuclear cells from three independent donor aspirations (BM-MSCs) and fresh umbilical cords collected from full-term births (WJ-MSCs) | SD rats i.p. injected with CCl4 at a dose of 2 ml/kg (CCl4:olive oil = 1:1) twice a week for the first 2 weeks, followed by 1 ml/twice a week for the next 6 weeks | Reduction of liver collagen content and improvement of liver architecture, by secreting fibrinolytic metalloproteases, such as MMP-1 and MMP-2 | Rengasamy et al., 2017 |
| Rat BM-MSCs | Tibia and fibula of white albino rats | 0.2 ml/100 g of CCl4 liquefied in castor oil (40 ml/L) subcutaneously injected twice weekly for 6 weeks in male 6-week-old white albino rats | Recovery of liver function and improved liver fibrosis with prolonged presence of transplanted BM-MSCs in the liver: reduction in the expression of pro-inflammatory cytokines (IL-1β, IL-6, and IFN-γ) and of pro-fibrogenic factors (TGF-β1, α-SMA, and CTGF) and increase in the expression of anti-fibrogenic factors (CK-18 and HGF) | Idriss et al., 2018 |
| Rat BM-MSCs transfected with human MMP-1 | BM of SD rats | CCl4 administration in rats at a dose of 1 ml/kg twice/week for 8 weeks | Degradation of hepatic collagen due to significant increased MMP-1 level and suppression of TIMP-1 | Du et al., 2018 |
| Rat BM-MSCs | Tibia and femur of rats | Rats i.p. injected with CCl4 (1 ml/kg) dissolved in paraffin oil, twice a week, for 6 weeks (12 doses) | Significant downregulation of Col1a1, AFP, and STAT3 and STAT5 gene, whereas significant improvement of Alb expression | Farouk et al., 2018 |
| Human BM-MSCs cultured under hypoxic (5% O2; hypoMSCs) and normoxic (21% O2; norMSCs) conditions | Normo: Poietics human MSCs (passage 2) purchased from Lonza. Hypo: StemPro BM-MSCs from Thermo Fisher Scientific | In vitro: induced BM-derived co-cultured with MSCs in Transwell 6-well plates for 72 h. In vivo: 8-week-old C57BL/6 male mice injected with CCl4 i.p. twice weekly over a 12-week period | Induction of anti-inflammatory markers CD206 and Ym-1 in hypoMSC-treated macrophages. Downregulation of the pro-inflammatory markers TNFα and MCP-1 | Kojima et al., 2019 |
| BM-MSCs labeled with super-paramagnetic iron oxide nanoparticles | Femur of male SD albino rats | SD albino rats i.p. injected with CCl4 for 8 weeks | ECM degradation by increased MMP-1 and decreased TIMP-1 | Khalifa et al., 2019 |
| Murine BM-MSCs | Tibia and femur of mice C57BL/6 | C57BL/6 mice injected with CCl4 (40% in olive oil) at a dose of 1 ml/kg twice/week for 12 weeks | Amelioration of the hypoxic liver microenvironment, improvement of the liver function, and reduction of fibrosis by modulating the TGF-β1/SMADs signaling pathway: reduction of TGF-β1 and SMAD3 expression and increased SMAD7 expression | Zhang et al., 2019 |
| Human ADSCs | Human adipose tissue-derived stromal vascular fraction | Male NOD/SCID mice (NOD.CB17-Prkdcscid/J strain) i.p. injected with 200 mg/kg with TAA 2 times/week for 4 weeks | Induction of liver regeneration and amelioration of fibrosis and inflammation with downregulation of IL-1α, IL-6, and TNF-α and increased expression of HGF and VEGF-A | Choi et al., 2019 |
| Rat BM-MSCs + VEGF | Tibia and femur of 2-week-old SD rats | 8-week-old rats i.p. injected with 40% CCl4 at 0.3 ml/100, twice per week, for 12 weeks. VEGF group and the BMSC + VEGF group i.v. injected with VEGF over-expressing adenovirus at 3 × 109 ifu (0.5 ml), once a week for 4 weeks | Low amount of collagen deposition related to low IL-6 mRNA levels; high levels of VEGF and VCAM-1 expression in the hepatic sinusoidal endothelial cells | Yuan et al., 2019 |
| HLSCs | Liver fragment processed in Good Manufacturing Practice (GMP) procedure | NASH induced by MCDD | Significant improvement of liver function and morphology, at histological and molecular levels, by persistence of undifferentiated HLSCs in the liver that induce reduction of α-SMA, type I collagen, and TGF-β expression | Bruno et al., 2019 |
| hDPSCs | Deciduous teeth of healthy pediatric donors | C57BL/6J male, 8-week-old mice i.p. injected with 0.5 mg/kg of CCl4 in olive oil twice a week for 4 weeks | Liver regeneration induced by the in situ transformation of the transplanted hDPSCs, with reduced expression of ACTA2, Col1a1, and liver fibrosis-related genes and proteins: MMP-2, MMP-3, TIMP-1, TIMP-2, and TGF-β | Iwanaka et al., 2020 |
| BM-MSCs with recombinant adeno-associated virus expression vector encoding human HGF genome sequence (rAAV-HGF) | Stem Cell Bank of the Chinese Academy of Sciences (CAS) | SD rats fed with 5% ethanol and subcutaneously injected with 40% CCl4 diluted 1:1 (v/v) in olive oil (0.5 ml/kg) 3 times/week for 9 weeks | Reduction of fibrotic structure related to low expression of α-SMA, collagen I, and vimentin transcripts | Sun et al., 2020 |
| Rat ADSCs incubated with eugenol in olive oil (10 mg/ml) | Adipose tissue of 2-month-old male rats | SD-1 rats i.p. injected with 1 ml/kg of CCl4 diluted in olive oil 1:1 (v/v) twice a week for 6 weeks | Amelioration of liver function, reduction of fibrotic markers (type III collagen, hyaluronic acid, hydroxyproline) and inflammatory cytokines (TNF-α, IL-1β, and IL-6), by decreasing the mRNA levels of type 1 collagen, α-SMA, and TGF-β genes | Fathy et al., 2020 |