Use of mesenchymal stem cells to treat liver fibrosis: Current situation and future prospects

Table 1 Preclinical and clinical studies representing the development of anti-fibrotic strategies

Antifibrotic drug		Preclinical/clinical results	Disease model	Ref.
Downregulation of hepatic stellate cell (HSC) activation
	Peroxisomal proliferator-activated receptor gamma agonist (pioglitazone)	Inhibition of HSC activation and amelioration of hepatocyte necroinflammation in rats after 8 wk	Carbon tetrachloride (CCl4)-induced liver fibrosis	[44]
		Reduction of steatosis, but not fibrosis compared to placebo, in patients with NASH after 6 mo (26 pioglitazone; 21 placebo)	Nonalcoholic steatohepatitis (NASH)	[45]
		No benefit of pioglitazone over placebo in term of steatosis and fibrosis in patients with NASH after 96 wk (80 pioglitazone; 83 placebo)	NASH	[46]
	Interferon gamma (IFN-γ)	Inhibition of the activation of HSC and extracellular matrix production	CCl4-induced liver fibrosis	[47]
		Improvement of fibrosis scores in patients with chronic hepatitis B virus (HBV) infection after 9 mo (54 IFN-γ; 29 control)	Chronic HBV infection	[48]
	Antioxidant (vitamin E)	No reversion of fibrosis in patients with advanced liver disease after 1 yr (IFN-γ1b 100 μg 169; IFN-γ1b 200 μg 157; placebo 162)	Chronic hepatitis C virus (HCV) infection	[49]
		Protective effects against liver damage and cirrhosis in rats	CCl4-induced liver fibrosis	[50]
		No benefit on liver function tests in patients with mild to moderate alcoholic hepatitis after 1 yr (25 vitamin E, 26 placebo)	Alcoholic hepatitis	[51]
Neutralization of proliferative, fibrogenic and contractile responses of HSC
	Anti-transforming growth factor beta (TGF-β)	Supression of fibrosis in rats after 3 wk	Dimethylnitrosamine-induced liver fibrosis	[52]
	Short interference RNA	Inhibition of the expression of TGF-β1 and attenuation of liver fibrosis in rats	High-fat diet and CCl4-induced model of liver fibrosis	[58]
	Endothelin antagonist	Nonpeptide endothelin-A receptor antagonist, LU 135252, reduced collagen accumulation in rats after 6 wk	Secondary biliary fibrosis	[53]
	Angiotensin system inhibitor	Olmesartan, an angiotensin II type 1 receptor blocker, decreased expression of collagen genes and attenuated liver fibrosis in rats after 15 wk	Methionine-choline-deficient rat model of NASH	[54]
		Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-1 blocker (ARB) did not retard the progression of liver fibrosis in patients with advanced liver fibrosis after 3.5 yr (66 ACEi/ARB, 126 non-ACEi/ARB, 343 no antihypertensive medication)	Chronic hepatitis C	[55]
	Colchicine	Colchicine and colchiceine (metabolite of colchicine) prevented the increase in collagen synthesis and increased the intracellular degradation of collagen rats	CCl4-induced liver fibrosis	[56]
		Colchicine improved fibrosis marker expression, but not histological finding, in patients with hepatic fibrosis after 12 mo (21 colchicine; 17 control)	Liver fibrosis of various etiologies	[57]
Promotion of HSC apoptosis
	Gliotoxin	Morphologic alterations typical of HSC apoptosis in vitro (activated rat and human HSCs) and reduction of the number of activated HSCs in rats	CCl4-induced liver fibrosis	[59]
	Sulfasalazine	Induction of activated HSC apoptosis, by inhibiting nuclear factor kappa B-dependent gene transcription, both in vitro (activated rat and human HSC) and in vivo	CCl4-induced liver fibrosis	[60]
Promotion of matrix degradation
	Matrix metalloproteinase (MMP) inducer	Urokinase-type plasminogen activator, an initiator of the matrix proteolysis cascade, induced collagenase expression and reversal of fibrosis rats	CCl4-induced liver fibrosis	[61]
	Tissue inhibitor of matrix metalloproteinase (TIMP) inhibitor	Polaprezinc, a zinc-carnosine chelate compound, attenuated fibrosis by inhibiting TIMP expression during a later phase, thus promoting fibrinolysis, in mice after 10 wk	Dietary methionine and choline deficient (MCD)-induced NASH	[62]
Reduce inflammation
	Interleukin 10	Inhibition of HSC activation and decrease of the expression of TGF-β1, MMP-2, and TIMP-1 in rats	CCl4-induced liver fibrosis	[63]
		Anti-inflammatory effect, but increased HCV viral burden via alterations in immunologic viral surveillance, in patients (30 subjects for 3-dose trial)	Chronic hepatitis C	[64]
	Anti-tumour necrosis factor-α	Infliximab decreased necrosis, inflammation, and fibrosis in rats	Dietary MCD-induced NASH	[65]
		Infliximab improved Maddrey’s score in patients after 28 d (20 subjects)	Alcoholic hepatitis	[66]
	Ursodeoxycholic acid (UDCA)	Reversion of liver damage in rats	CCl4-induced liver fibrosis	[67]
		Reduction of periportal necroinflammation and, if initiated at the earlier stages I-II of the disease, delay of the progression of histologic stage in patients after 2 yr (200 UDCA, 167 placebo)	Primary biliary cirrhosis	[68]
Inhibition of collagen I cross-linking
	Anti-Lysyl oxidase-like-2	Reduction of liver fibrosis, decrease in the number of myofibroblasts and lower p-Smad3 signal	CCl4-induced liver fibrosis	[69]