Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies

Table 2 Strategies to enhance bone marrow-derived mesenchymal stem cell therapeutic efficiency

Ref.	Year	Pathogenesis	Model	Route	Strategy	Strategy efficiency
[117]	2020	CCl4	Mice	Tail vein	Preconditioning: Autophagy regulation in BM-MSCs	Boosted 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]	2019	CCL4	Rats	Tail vein	Preconditioning: Conditioned media	Increasing 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]	2016	CCl4	Rats	Tail vein	Preconditioning: With melatonin	Enhanced 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]	2017	CCI4	Rats	Tail vein	Preconditioning: With melatonin	High 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]	2019	CCL4	Rats	Tail vein	Cell-free therapy: MSC-derived macrovesicles BM- MSC-MVs	Increased 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]	2019	CCl4	Rats	Tail vein	Cell free therapy: hBM-MSCs-Ex	Inhibition of Wnt/β-catenin signaling (PPARγ, Wnt10b, Wnt3a, β-catenin)
						Downregulation of downstream gene expression (cyclin D1, WISP1)
[123]	2015	CCl4	Rats	Intravenous	Genetically modified BM-MSCs expressing TIMP-1-shRNA	Decreased 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]	2020	CCl4	Mice	Intraperitoneal injection	MSCs expressing EPO	Promoted cell viability and migration of BM-MSCs
						Enhanced antifibrotic efficacy with higher cell viability and stronger migration ability
						Alleviated liver fibrosis
[125]	2015	BDL or CCl4	Mice	Underneath the kidney capsule	Microencapsulated BM-MSCs	Activated 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]	2018	CCl4	Rats	Tail vein	Genetically modified BM-MSCs with human MMP-1	Biochemical parameters and hepatic architecture improved
						Decreased collagen content
						Suppressed activation of HSCs
						Improvement of both liver injury and fibrosis
[127]	2016	CCl4	Rats	Tail vein	Human urokinase-type plasminogen activator gene-modified BM-MSCs	Decreased serum levels of ALT, AST, total bilirubin, hyaluronic acid, laminin, and procollagen type III
					Genetically modified BM-MSCs with human urokinase-type plasminogen activator	Increased 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]	2015	TAA	Mice	Tail vein	Genetically modified BM-MSCs, MSCs engineered to produce IGF-I	Enhanced 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]	2017	CCl4, BDL	Mice	Intraperitoneal	BM-MSCs triggered by sphingosine 1-phosphate	Increased 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

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BDL: Bile duct ligation; BM-MSCs: Bone marrow-mesenchymal stem cells; CCl4: Carbon tetrachloride; EPO: Erythropoietin; hBM-MSCs-Ex: Human BM-MSCs-exomes; HBM: Human bone marrow; HGF: Hepatocyte growth factor; HSCs: Hepatic stellate cells; IGF-I: Insulin growth factor like-I; IL: Interleukin; MMPs: Matrix metalloproteinases; MSCs: Mesenchymal stem cells; MT: Melatonin; MVs: Microvesicles; PGE2: Prostaglandin E2; PPARγ: Peroxisome proliferator-activated receptor-gamma; PTGS2: Prostaglandin-endoperoxide synthase-2; S1P: Sphingosine 1-phosphate; S1PR3: Sphingosine-1-phosphate receptor 3; TGF: Transforming growth factor; TIMP-1: Tissue inhibitor of metalloproteases 1; UTR: Untranslated region; VEGF: Vascular endothelial growth factor; WISP1: Wnt-1-induced secreted protein 1.