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

Table 1 Bone marrow-derived mesenchymal stem cell therapeutic efficiency compared to other treatments and other stem cell sources

Ref.	Year	Pathogenesis	Model	Route	BM-MSCs compared to	Effect on liver fibrosis	Efficiency comparison
[107]	2020	CCl4	Rats	Penile vein	Standard therapy: resveratrol and silybum marianum	Decreased AST, ALT, MDA, ALP, TNF-α, and CYP450 and increased albumin, SOD, GSH, GST, and CAT	BM-MSCs were more efficient
						Restored liver structure and function and markedly decreased the induced liver fibrosis
[108]	2020	CCl4	Rats	Intravenous	Imatinib	High therapeutic potential of utilizing BM-MSCs and imatinib, either individually or combined	Combined 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]	2018	TAA	Rats	Right lobe of the liver	Simvastatin	Reduced TGF-β1, α-SMA, and collagen-1 expression	Combined treatment was more efficient
						Inhibited TGF-β/Smad signaling
						Sim-MSCs strongly inhibited the progression of TAA-induced hepatic fibrosis
[110]	2016	TAA	Rats	Intrahepatic	Decorin	DCN and BM-MSCs alleviated liver fibrosis through: (1) decreased proliferation of HSCs; (2) suppressed TGF-β/Smad signaling; and (3) antifibrotic effect	Combined treatment was more efficient
[111]	2016	CCl4	Rats	Intravenous	Endothelial progenitor cells	Elevated albumin and reduced ALT concentrations	No 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]	2020	CCl4	Rats	Tail vein	Human UC CD34+	Expressing liver-specific genes	BM-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]	2017	CCl4	Rats	Intravenous	WJ-MSCs	Decreased hepatic hydroxyproline content and the percentage of collagen proportionately	BM-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]	2017	CCI4	Rats	Portal vein	AD-MSCs	Prevented 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]	2018	CCl4	Rats	Intravenous and intrasplenic	Intravenous and intrasplenic route	Elevated serum albumin levels and reduced serum ALT levels	Intravenous 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]	2016	CCl4	Mice	Portal and tail vein	Tail and portal vein route	Reduced AST/ALT levels	There were no efficiency differences
						Stimulated positive changes in serum bilirubin and albumin
						Downregulated expression of integrins (600-7000-fold), TGF, and procollagen-α1

α-SMA: Alpha-smooth muscle actin; a-SMA: Anti-alpha-smooth muscle actin; AD-MSCs: Adipose-derived mesenchymal stem cells; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; BM-MSCs: Bone marrow-mesenchymal stem cells; CAT: Catalase; CCl4: Carbon tetrachloride; CK18: Cytokeratin 18; CTGF: Connective tissue growth factor; CYP450: Cytochrome P450; DCN: Decorin; GSH: Glutathione reductase; GST: Glutathione S-transferase; HGF: Hepatocyte growth factor; HSCs: Hepatic stellate cells; IL-1β: Interleukin-1β; IL-6: Interleukin 6; MDA: Malondialdehyde; MMP: Matrix metalloproteinase; MSCs: Mesenchymal stem cells; Sim-MSCs: Simvastatin-mesenchymal stem cells; SOD: Superoxide dismutase; TAA: Thioacetamide; TGF-β: Transforming growth factor-beta; TNF-α: Tumor necrosis factor-alpha; UC CD34+: Umbilical cord blood CD34+; UC-EPCs: Umbilical cord-endothelial progenitor cells; WJ-MSCs: Wharton’s jelly-derived mesenchymal stem cells; VEGF: Vascular endothelial growth factor.

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.