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.