Stem cells for liver tissue repair: Current knowledge and perspectives

Table 1 Representative studies investigating in vitro and/or in vivo hepatocyte differentiation of MSCs

Cell source	In vitrodifferentiation	In vivodifferentiation	References
Human BM&UCB immunoselection	Cocktail: EGF-bFGF (2 d), HGF-bFGF-nicot (7 d), OSM-dexa-ITS Characterization: RT-PCR (8), ICC (2), urea production, LDL uptake, PROD	ND	Lee et al[8]
Human UCB	ND	Host: preimmune fetal sheep Injury: - Cell characterization: Alb+, HepPar1+ Fusion: microdissection + PCR: - Repopulation rate: > 20%	Kögler et al[16]
Human adipose tissue	Cocktail: DMSO-HGF-OSM Characterization: RT-PCR (4), ICC (1), urea production, LDL uptake	Host: NOD/SCID mice Injury: CCl4 TRP: 1.106 cells, tail vein Cell characterization: Alb+/CM-Dil+ Repopulation rate: up to 0.13% Alb+ at 10 d	Seo et al[22]
Human BM MSCs, CD34+ cells, non MSCs/CD34- cells	ND	Host: WT rats (+CsA) Injury: AA TRP: 1.106 cells, liver Cell characterization: Alb+, CK18+, CK19+, αFP+, AGPR+, serum Alb+ Fusion: FISH hum Y/rat chr 12: -	Sato et al[21]
Human BM	Cocktail: 5'aza (1 d) - EGF-EGF (14 d) Characterization: RT-PCR (11), ICC (4), WB (4), urea production, PAS, reporter gene construct for PEPCK activity	Host: Pfp/Rag2-/- mice Injury: propanolol, partial hepatect TRP: 1.106 cells, liver Cell characterization: Alb+, HepPar-1+, PEPCK+, CX32+, PAS+ Fusion: FISH hum alu/mouse satellite: -	Aurich et al[10]
Human BM	Cocktail: HGF-FGF4-ITS-nicot (7 d), OSM-dexa-ITS (15 d) Characterization: RT-PCR (17), ICC (8), flow cytometry, urea&Alb production, PAS, G6Pase activity, neoglucogenesis	Host: SCID mice Injury: partial hepatect or retrorsine/AA TRP: 1.106 cells, spleen or liver Cell characterization: Alb+, αFP+, CK18+, fibronectin+, vimentin+, hum alu+	Lysy et al[106]

Alb: Albumin; AA: Allyl alcohol; αFP: Alpha-fetoprotein; CCl₄: Carbon tetrachloride; CB: Cord blood; CK: Cytokeratin; CsA: Ciclosporin A; d: Days; dexa:Dexamethasone; FGF: Fibroblastic growth factor; G6Pase: Glucose-6-phosphatase; hepatect: Hepatectomy; HGF: Hepatocyte growth factor; hum: Human; ITS: Insulin-transferrin-selenium; nicot: Nicotinamide; OSM: Oncostatin M; PAS: Periodic acid-schiff; PEPCK: Phosphoenolpyruvate carboxykinase; PROD: Pentoxyresorufin-O-dealkylase; WT: Wild-type; chr: Chromosome; FISH: Fluorescent in situ hybridization; ICC: Immunocytochemistry; ND: Not documented; RT-PCR: Reverse transcription-polymerase chain reaction; TRP: Transplantation; WB: Western blot. Amounts of analyzed markers are provided between brackets.

Table 2 Representative studies investigating in vitro and/or in vivo hepatocyte differentiation of HSCs

Cell source	In vitrodifferentiation	In vivodifferentiation	References
Mouse BM	ND	Host: irradiated FAH-/- mice Injury: NTBC withdrawal TRP: 10 to 1000 cells; retroorbital plexus Cell characterization: β-gal+, Alb+, DPPIV+, e-cadherin+, FISH Y+, liver function, FAH activity Repopulation rate: 30%-50% βgal+ cells	Lagasse et al[73]
Mouse BM	ND	Host: irradiated CD45.1+ mice Injury: hepatect or anti-Fas Ab treatment TRP: 106 cells; vein Cell characterization: CK8+, CK18+, CK19+, CD45.2+, FISH Y+, PCR Bcl-2+ Repopulation rate: up to 0.05%-0.8% with anti-Fas Ab treatment	Mallet et al[74]
Human UCB&BM	ND	Host: irradiated NOD/SCID mice ± HGF Injury: CCl4 TRP: 2000 to 105 cells; vein Cell characterization: Alb+, CD45-, human alu+, CK19+, Alb mRNA+, serum Alb+ Repopulation rate: < 1%	Wang et al[77]
Human UCB&PB	ND	Host: irradiated NOD/SCID mice Injury: CCl4 TRP: 2 to 6 × 105 CD34+ cells; tail vein Cell characterization: CD45+, Alb+, α1-AT+, hum DNA+, hum Alb mRNA+&prot+ Repopulation rate: ≤ 0.01% hum Alb mRNA in mice vs human liver	Kollet et al[70]
Mouse BM	Cocktail: co-culture with damaged liver tissue Characterization: RT-PCR (8), ICC (10), FISH Alb mRNA	Host: mice ± irradiation Injury: CCl4 TRP: 105 cells; tail vein Cell characterization: Alb+, FISH Y+, E-cadh+, PKH26+, serum liver function Repopulation rate: up to 7.6% at 2 d Fusion: FISH X-Y: -	Jang et al[69]
Mouse BM	ND	Host: mice ± irradiation ± rhG-CSF Injury: partial hepatect or CCl4 TRP: 5 × 103 selected cells or 5 × 105 MNCs; spleen Cell characterization: no co-eGFP/DPPIV staining, PCR eGFP- Repopulation rate: 0/6.9 × 107 host hepatocytes	Cantz et al[65]

α1-AT: Alpha-1-antitrypsin; Ab: Antibody, Alb: Albumin; β-gal: β-galactosidase; BM: Bone marrow; CCl₄: Carbon tetrachloride; CK: Cytokeratin; d: Days; dexa: Dexamethasone; DPPIV: Dipeptidyl peptidase IV; eGFP: Enhanced green fluorescent protein; FAH: Fumarylacetoacetate hydrolase; hepatect: Hepatectomy; HGF: Hepatocyte growth factor; hum: Human; MNCs: Mononuclear cells; ND: Not documented; NTBC: 2-2nitro-4-trifluoromethylbezoyle-1,3-cyclohexanedione; PB: Peripheral blood; UCB: Umbilical cord blood; E-cadh: E-cadherin; rhG-CSF: Recombinant human Granulocyte-Colony Stimulating Factor; TRP: Transplantation. Amounts of analyzed markers are provided between brackets.