Copyright ©The Author(s) 2020.
World J Gastroenterol. Dec 21, 2020; 26(47): 7444-7469
Published online Dec 21, 2020. doi: 10.3748/wjg.v26.i47.7444
Table 1 Bone marrow-derived mesenchymal stem cell therapeutic efficiency compared to other treatments and other stem cell sources
Ref.YearPathogenesisModelRouteBM-MSCs compared toEffect on liver fibrosisEfficiency comparison
[107]2020CCl4RatsPenile veinStandard therapy: resveratrol and silybum marianumDecreased AST, ALT, MDA, ALP, TNF-α, and CYP450 and increased albumin, SOD, GSH, GST, and CATBM-MSCs were more efficient
Restored liver structure and function and markedly decreased the induced liver fibrosis
[108]2020CCl4RatsIntravenousImatinibHigh therapeutic potential of utilizing BM-MSCs and imatinib, either individually or combinedCombined treatment was the most efficient
Reduced serum levels of ALT, AST, and ALP concomitantly
Downregulated α-SMA, procollagen I, procollagen III, collagen IV, and laminin
[109]2018TAARatsRight lobe of the liverSimvastatinReduced TGF-β1, α-SMA, and collagen-1 expressionCombined treatment was more efficient
Inhibited TGF-β/Smad signaling
Sim-MSCs strongly inhibited the progression of TAA-induced hepatic fibrosis
[110]2016TAARatsIntrahepaticDecorinDCN and BM-MSCs alleviated liver fibrosis through: (1) decreased proliferation of HSCs; (2) suppressed TGF-β/Smad signaling; and (3) antifibrotic effectCombined treatment was more efficient
[111]2016CCl4RatsIntravenousEndothelial progenitor cellsElevated albumin and reduced ALT concentrationsNo statistically significant difference
UC-EPCs were more valuable in increasing gene expression of HGF and immunohistochemistry of α-SMA and Ki-67; BM-MSCs had significantly lower TGF-β compared to UC-EPCs
[112]2020CCl4RatsTail veinHuman UC CD34+Expressing liver-specific genesBM-MSCs were less efficient
Decreased gene expression of profibrotic genes (collagen Iα, TGFβ1, α-SMA) and of albumin
Increased antifibrotic gene (MMP-9) expression and decreased proinflammatory gene (TNF-α) expression
Reduced ALT concentration
[113]2017CCl4RatsIntravenousWJ-MSCs Decreased hepatic hydroxyproline content and the percentage of collagen proportionatelyBM-MSCs were more efficient
Reduced α-SMA and myofibroblasts
Increased number of EpCAM+ hepatic progenitor cells along with Ki-67+ and human matrix metalloprotease-1+ (MMP-1+) cells
[114]2017CCI4RatsPortal veinAD-MSCsPrevented activation and proliferation of HSCs, and promoted apoptosis of HSCs Similar efficiency
Implantation of AD-MSCs exhibited slightly improved anti-inflammatory and antiliver fibrotic activities compared to BM-MSCs
[115]2018CCl4RatsIntravenous and intrasplenicIntravenous and intrasplenic routeElevated serum albumin levels and reduced serum ALT levelsIntravenous route was more efficient
Decreased inflammation by reducing the gene expression of proinflammatory cytokines (IL-1β, IL-6, and INF-γ)
An antifibrotic effect via reduced profibrogenic factors (TGF-β1, α-SMA, CTGF) and increased antifibrogenic factors (CK18, HGF)
Increased VEGF protein levels
[116]2016CCl4MicePortal and tail veinTail and portal vein routeReduced AST/ALT levelsThere were no efficiency differences
Stimulated positive changes in serum bilirubin and albumin
Downregulated expression of integrins (600-7000-fold), TGF, and procollagen-α1
Table 2 Strategies to enhance bone marrow-derived mesenchymal stem cell therapeutic efficiency
Ref.YearPathogenesisModelRouteStrategyStrategy efficiency
[117]2020CCl4MiceTail veinPreconditioning: Autophagy regulation in BM-MSCsBoosted antifibrotic potential primed by autophagy inhibition in BM-MSCs may be attributed to their suppressive effect on CD4+ and CD8+ lymphocytes infiltration and HSC proliferation, which were regulated by elevated PTGS2/PGE2 via a paracrine pathway
BM-MSC-based remedy in liver fibrosis and other inflammatory disorders
[118]2019CCL4RatsTail veinPreconditioning: Conditioned mediaIncreasing antioxidant enzyme activity
Increased gene expression levels attenuated by CCl4 up to basal levels
Normalized the organization apart from some dilated sinusoids and vacuolated cells
Improved morphological, immunohistochemical, and biochemical measures
[119]2016CCl4RatsTail veinPreconditioning: With melatoninEnhanced homing ability of MSCs
Enhanced liver function
Enhanced the interaction of melatonin receptors and matrix enzymes
Expressed a high level of CD44
Ability to differentiate into adipocytes and Schwann cells
[120]2017CCI4RatsTail veinPreconditioning: With melatoninHigh ability of homing into the injured liver (P ≤ 0.05 vs BM-MSCs)
Higher percentage of glycogen storage but a lower percentage of collagen and lipid accumulation (P ≤ 0.05 vs CCl4 + BM-MSCs)
Low expression of TGF-β1 and Bax and lower content of serum ALT but higher expressions of MMPs and Bcl2
The effectiveness of MT preconditioning in cell therapy
[121]2019CCL4Rats Tail veinCell-free therapy: MSC-derived macrovesicles BM- MSC-MVsIncreased serum albumin levels and VEGF quantitative gene expression (P < 0.05)
Decreased serum ALT enzyme levels, quantitative gene expression of TGF-β, collagen-1α, and IL-1β
Decreased the collagen deposition and improvement of the histopathological picture
Antifibrotic, anti-inflammatory, and proangiogenic effects
[122]2019CCl4RatsTail veinCell free therapy: hBM-MSCs-ExInhibition of Wnt/β-catenin signaling (PPARγ, Wnt10b, Wnt3a, β-catenin)
Downregulation of downstream gene expression (cyclin D1, WISP1)
[123]2015CCl4RatsIntravenousGenetically modified BM-MSCs expressing TIMP-1-shRNADecreased TIMP-1 expression thereby regulating HSC survival
Decreased serum levels of ALT and AST, fibrotic areas, and collagens
Reduction of the fibrotic area
Restoration of the liver function
[124]2020CCl4MiceIntraperitoneal injectionMSCs expressing EPOPromoted cell viability and migration of BM-MSCs
Enhanced antifibrotic efficacy with higher cell viability and stronger migration ability
Alleviated liver fibrosis
[125]2015BDL or CCl4MiceUnderneath the kidney capsuleMicroencapsulated BM-MSCsActivated HSCs
Released antiapoptotic (IL-6, IGFBP-2) and anti-inflammatory (IL-1Ra) cytokines
Decreased mRNA levels of collagen type I
Increased levels of MMPs
[126]2018CCl4RatsTail veinGenetically modified BM-MSCs with human MMP-1Biochemical parameters and hepatic architecture improved
Decreased collagen content
Suppressed activation of HSCs
Improvement of both liver injury and fibrosis
[127]2016CCl4RatsTail veinHuman urokinase-type plasminogen activator gene-modified BM-MSCsDecreased serum levels of ALT, AST, total bilirubin, hyaluronic acid, laminin, and procollagen type III
Genetically modified BM-MSCs with human urokinase-type plasminogen activatorIncreased levels of serum albumin
Downregulated both protein and mRNA expression of β-catenin, Wnt4, and Wnt5a
Decreased the Wnt signaling pathway
Decreased mRNA and protein expression of molecules involved in Wnt signaling thus working as an antifibrotic
[128]2015TAAMiceTail veinGenetically modified BM-MSCs, MSCs engineered to produce IGF-IEnhanced the effects of MSC transplantation
Decreased inflammatory responses
Decreased collagen deposition
Increased growth factor like-I, IGF-I, and HGF
Reduced fibrogenesis and the stimulation of hepatocellular proliferation
[129]2017CCl4, BDLMiceIntraperitonealBM-MSCs triggered by sphingosine 1-phosphateIncreased HuR expression and cytoplasmic localization
S1P-induced migration of HBM-MSCs via S1PR3 and HuR
HuR regulated S1PR3 mRNA expression by binding with S1PR3 mRNA 3’ UTR
S1P-induced HuR phosphorylation and cytoplasmic translocation via S1PR3
HuR regulated S1PR3 expression by competing with miR-30e