Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

Table 2 Mesenchymal stem/stromal cells-derived extracellular vesicles in experimental models of liver disease

Ref.	EVs Isolation/characteristics	Experimental model	Protocol	Biological effects
Haga et al[98] 2016	Ultracentrifugation Size: 46-116 nm Alix+ CD9+, CD81+	C57Bl mice. ALF, i.p. 20 mg/body DGalNAc + 0,3 mg/body TNF-α	2 × 108 to 2 × 1010 i.p./i.v.	↑ Survival, ↑ F4/80, ↑ inhibitor MMP-1 and IL-6, ↓ inflammation and apoptosis, ↓ ALT/AST, ↓ ALP, ↓ EGF, SCF, IFN-γ, IP-10, IL-1α, MIP3, MCP-1/3
Yan et al[100] 2016	Ultracentrifugation Size: 30-100 nm CD9+, CD61+, CD63+	BALB/c-nu/nu mice, i.p. CCL4induced ALF, 0.15-0.35 mL/kg	8, 16, and 32 mg/kg i.v./oral	↓ Oxidative stress and apoptosis Induces ERK1/2 phosphorylation and Bcl2 expression Inhibits IKKB/NFκB/casp9/3 pathway
Tan et al[99] 2014	TFF, 100.kDa MWCO filter Size: 55-100 nm	C57BL/6 mice. CCL4-induced ALF, i.p. 0.05 mL CCL4/kg	0.4 μg (100 μL) i.s.	↑ Cell viability: TAMH, THLE-2, and Huh-7 ↑ Hepatocytes proliferation ↓ ALT/AST ↓ Casp 3/7 ↑ antiapoptoticBcl-xL
Chen et al[97] 2017	Centrifugation and Exoquick-TC Size: 30-100 nm CD63+ and tsg101+	C57BL/6 mice. ALF, i.p. D-GalNAc 800 mg/kg and LPS 50 μg/kg	1 μg/μL i.v.	↑ Liver function and survival ↓ Apoptosis ↓ TNF-α, IL-6 and IL-1 ↓ Casp-3 ↓ Necrosis and inflammation
Nong et al[101] 2016	Ultracentrifugation and ultrafiltration Size: 50-60 nm CD9+, CD63+ and CD81+	Rats I/R injury	600 μg suspended in 400 μL of PBS i.v.	↑ GSH, GSH-PX and SOD ↓ AST/ALT ↓ TNF-α, IL-6 and HMGB1 ↓ Casp-3 and Bax
Du et al[93] 2017	Centrifugation and filtered by 0, 45-μm PVDF filter ExoQuick Size: 100-200 nm Alix+, CD63+ and CD81+	C57 mice I/R injury	2.5 × 1012 particles in 500 μL of PBS i.v.	↑ Hepatocytes proliferation ↑ SK activity and S1P formation. Hepatoprotective and proliferative effect abolished by the inhibition of SK or S1P receptor 1

i.p.: Intraperitoneal injection; i.v.: Intravenous injection; i.s.: Intrasplenic; MMP: Metalloproteinases; CCL₄: Corbon tetrachloride; D-GalNAc: N Acetylgalactosamine; IL: Interleukins; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; EGF: Epidermal growth factor; SCF: Stem cell factor; TNF: Tumor necrosis factor; IFN: Interferon; IP: Inducible protein; MIP: Macrophage inflammatory protein; MCP: Monocyte chemotactic protein; ERK: Extracellular signal-regulated kinase; Bcl: B-cell lymphoma; TFF: Tangential flow filtration; MWCO: Molecular weight cut-off; ALF: Acute liver failure; TAMH: Transgenic mouse hepatocyte; THLE: T-antigen immortalized human liver epithelial; Casp: Caspase; GSH: Glutathione; GSH-PX: Glutathione peroxidase; SOD: Superoxide dismutase; HMGB: High mobility group box; PBS: Phosphate-buffered saline; SK: Sphingosine kinase; S1P: Sphingosine 1-phosphate.