Current understanding of mesenchymal stem cells in liver diseases

Table 1 Experiments using mesenchymal stem cell transplantation in animals

Disease	Treatment	Source	Animal	Main results	Mechanism	Ref.
ALF	APAP	Human UC-MSCs	Mice	Alleviate hepatic injury and improve survival rates	Mediate paracrine effects, regulate inflammatory response	Liu et al[38], 2014
ALF	LPS	Human UC-MSCs	Monkeys	Improve the hepatic histology, systemic homeostasis, and survival	Suppress the hepatic aggregation and maturation of circulating monocytes and their IL-6 secretion	Guo et al[40], 2019
LC	CCl4	Human UC-MSCs	Rats	Improve liver transaminases and synthetic function, reduce liver histopathology, and reverse hepatobiliary fibrosis	Differentiate into hepatocytes	Zhang et al[3], 2017
LC	CCl4	Monkey BM-MSCs	Mice	Decrease liver fibrosis, progression, and hepatocyte necrosis	Mediate paracrine effects	Fu et al[42], 2018
LC	TAA	Human BM-MSCs	Rats	Decrease collagen proportionate area and the content of hepatic hydroxyproline	Mediate TGF-β1/Smad signaling pathway	Jang et al[41], 2014
NAFLD	HFD	Mice BM-MSCs	Mice	Decrease fibrosis markers and pro-inflammatory cytokines	Regulate inflammatory process	Ezquer et al[46], 2011
NAFLD	HFD	Mice BM-MSCs	Mice	Decrease weight gain, expansion of subcutaneous adipose tissue, steatosis, lobular inflammation, and liver fibrosis	Suppress the proliferation of CD 4+ T cells	Wang et al[47], 2018

MSCs: Mesenchymal stem cells; AFL: Acute liver failure; LC: Liver cirrhosis; NAFLD: Non-alcoholic fatty liver disease; APAP: Acetaminophen; LPS: α-amatoxin and lipopolysaccharide; TAA: Thioacetamide; HFD: High-fat diet; BM-MSCs: Bone marrow-derived MSCs; UC-MSCs: Umbilical cord-derived MSCs.

Table 2 Clinical trials using mesenchymal stem cells to treat liver disease

Disease	Phase	No.	Stage	Source	Dose	Route of delivery	Main results	Ref.
LC	I–II	8	MELD score ≥ 10	Autologous BM-MSCs	30-50 million cells	Peripheral or the portal vein	Reduce volumes of ascites; improve MELD scores, INR, and serum creatinine	Kharaziha et al[64], 2009
LC	I–II	30	MELD Na score approximately 14	UC-MSCs	0.5 × 106 cells/kg	Peripheral	Reduce volumes; improve ALB, TBIL, PTA, and MELD Na scores	Zhang et al[65], 2012
ALC	II	48	Child-Pugh B/C	BM-MSCs	5 × 107 cells/kg	Hepatic artery	Improve Child-Pugh scores and histologic fibrosis	Suk et al[66], 2016
Liver failure	II	53	MELD score: CG: 29.15 ± 3.72; EG: 30.01 ± 3.99	Autologous BM-MSCs	None	Hepatic artery	Improve ALB, TBIL, PT, and MELD scores	Peng et al[67], 2011
ACLF	II	56	17 ≤ MELD score ≤ 30	Allogeneic BM-MSCs	1.0-10 × 105 cells/kg	Peripheral veins	Improve ALT, ALB, TBIL, and MELD scores; decrease mortality	Lin et al[69], 2017
ACLF	II	24	MELD score: CG: 26.32; EG: 24.05	UC-MSCs	0.5 × 106 cells/kg	Cubital vein	Improve ALB, CHE, PTA, and MELD score; increase survival rate	Shi et al[70], 2012

LC: Liver cirrhosis; ALC: Alcoholic liver cirrhosis; ACLF: Acute-on-chronic liver failure; CG: Control group; EG: Experimental group; BM-MSCs: Bone marrow-derived MSCs; UC-MSCs: Umbilical cord-derived MSCs; MELD: End-stage liver disease; ALB: Albumin; ALT: Alanine aminotransferase; TBIL: Total bilirubin; PT: Prothrombin time; PTA: Prothrombin time activity; INR: International normalized ratio; CHE: Cholinesterase.