Application of stem cells in the precise diagnosis and treatment of liver diseases

Table 1 Differentiation of human pluripotent stem cells into hepatic parenchymal and non-parenchymal cells

Liver lineages	Stem cell types	Culture medium	Supplements	Days of induction	Biomarkers	Ref.
Hepatocyte-like cells	hiPSCs	RPMI/B27, KO-DMEM with KSR, IMDM	Activin A, Wnt3a, HGF, OSM, Dex, ITS premix	12 days	AFP, albumin, CK18, HNF4, CYP3A4, CYP7A1	Chen et al[76]
Hepatocyte-like cells	hiPSCs	Hepatocyte culture medium, IMDM, N2/B27	Acitivin A, FGF4, BMP2, HGF, KGF, OSM, Dex	21 days	AFP, albumin, CK8, CK18, CK19, PEPCK, HNF4α, HNF6, CEBPα, GATA4, HEX	Song et al[75]
Hepatocyte cells	GATA6- hiPSCs	StemFit04, IMDM/Ham’s F-12K, N2/B27	L-ascorbic acid, Dex, 2-phosphate, basic fibroblast growth factor, 1-thioglycerol, HGF, nicotinamide, OSM	18 days	Albumin, AAT, AFP, HNF4A, CYP3A4, CYP3A5	Luo et al[126]
Hepatic cells	hESCs	DMEM/F12, KSR, 1640 medium	Activin A, aFGF, basic fibroblast growth factor, FGF4, HGF, BMP2, BMP4, Noggin, OSM, Dex, Su5402	18 days	PEPCK, CYP7A1, CYP3A4, CYP2B6	Cai et al[74]
Hepatocytes	hPSCs	DEI medium A/B, CDM3 medium, CDM5 medium	A8301, FGF2, Acitivin A, BMP4, ATRA, AAP, TTNPB, OSM, insulin, forskolin, SB505124, 8-bromo-cAMP, DAPT, CHIR99021, AA2P, RO4929097, Dex	18 days	Fumarylacetoacetate hydrolase, albumin, HGD	Ang et al[71]
Hepatic stellate cells	hiPSCs	Liver differentiation medium	BMP4, FGF1, FGF3, retinol, palmitic acid	12 days	PDGFRβ, PCHD7, COL1α1	Vallverdú et al[2]
Hepatic stellate cells	hPSCs	DMEM low glucose	BMP4, FGF1, FGF3, retinol, palmitic acid, ITS, Dex	12 days	DES, P75NTR, ALCAM, ACTA2, COL1α1, LRAT, RELN, PCDH7, PDGFRβ	Coll et al[91]
Hepatic stellate cells	hESCs	DMEM/F-12, B27, FBS	Activin A, CHIR99021, BMP4, FGF1, FGF3, Y-27632, palmitic acid, retinol	12 days	PDGFRβ, NCAM1, ALCAM, LRAT, ACTA2, vimentin	Wilhelmsen et al[92]
LSECs	hPSCs	EBM-2 medium, IMDM	BMP4, basic fibroblast growth factor, VEGF-A, CHIR99021, cAMP, GSI, SB431542, ITS-X, ascorbic acid, transferrin	22 days	CD34, PECAM1, VWF, LYVE1, CD14, FCGR2B, CD36, CD54, STAB1, FVIII, STAB2, CLEC1B	Gage et al[97]
LSECs	hPSCs	IMDM, DMEM-F12, StemPro34, FCS	BMP4, Activin A, ascorbic acid, basic fibroblast growth factor, L-685-458, ITS-X, VEGF-A, CHIR99021, transferrin	21 days	FCGR2B, LYVE1, STAB2, F8, CD14, MRC1, CD36, RAMP3, CD32B, FVIII	Gage et al[96]
LSECs	Mouse ESCs	IMEM, EGM2-MV, FBS	Adrenomedullin, SB431542, β-ME, VEGF-A, ITS	20 days	F8, Fcgr2b, Mrc1	Arai et al[100]
Cholangiocytes	hPSCs	RPMI 1640 medium, low glucose DMEM, B27, DMEM/F12, a-MEM	MTG, Acitivin A, CHIR99021, ascorbic acid, basic fibroblast growth factor, BMP4, HGF, EGF, OSM, Dex, RA, Noggin, Y-27632, forskolin	49 days	Albumin, AFP, CFTR, TRPV4, PKD1, PKD2	Ogawa et al[101]
Cholangiocytes	hiPSCs	RPMI, B27, William’s E medium	Acitivin A, FGF2, FGF10, BMP4, Ly294002, SB431542, RA, EGF	26 days	SSTR2, ALP, KRT7, SOX9	Sampaziotis et al[102]
Kupffer cells	hiPSCs	X-VIVO 15 media, PHCM, advanced DMEM	M-CSF, IL-3, streptomycin	4-5 weeks	CD163, CD200R, CD86, IL-6, CSF1, HLA-DRB1, IL-1β	Tasnim et al[106]
Kupffer cells	hESCs; cord blood	DMEM/F12, KSR, IMDM, RPMI 1640	BMP4, basic fibroblast growth factor, Activin A, IL-3, IL-7, M-CSF, TPO, SCF	9-17 days (cord blood); > 90 days (hESCs)	MARCO, CD5 L, TIMD4, VCAM1, CPVL, VSIG4, FOLR2, CD163	Kent et al[99]

LSECs: Liver sinusoidal endothelial cells; hiPSCs: Human induced pluripotent stem cells; hESCs: Human embryonic stem cells; hPSCs: Human pluripotent stem cells; ESCs: Embryonic stem cells; KO-DMEM: Knockout Dulbecco’s modified eagle medium; KSR: Knockout serum replacement; IMDM: Iscove’s modified Dulbecco’s medium; CDM3: Chemically defined medium 3; CDM5: Chemically defined medium 5; FBS: Fetal bovine serum; EBM-2: Endothelial basal medium-2; FCS: Fetal calf serum; IMEM: Iscove’s modified eagle medium; EGM2-MV: Endothelial growth medium-2 microvascular; a-MEM: Minimum essential medium alpha modification; PHCM: Primary hepatocyte culture medium; HGF: Hepatocyte growth factor; OSM: Oncostatin M; Dex: Dexamethasone; ITS: Insulin-transferrin-selenium; FGF4: Fibroblast growth factor 4; BMP2: Bone morphogenetic protein 2; KGF: Keratinocyte growth factor; aFGF: Acidic fibroblast growth factor; BMP4: Bone morphogenetic protein 4; FGF2: Fibroblast growth factor 2; ATRA: All-trans retinoic acid; AAP: Ascorbic acid 2-phosphate; AA2P: Ascorbic acid 2-phosphate; FGF1: Fibroblast growth factor 1; FGF3: Fibroblast growth factor 3; VEGF-A: Vascular endothelial growth factor A; cAMP: Cyclic adenosine monophosphate; GSI: Gamma-secretase inhibitor; ITS-X: Insulin-transferrin-selenium-X; β-ME: Β-mercaptoethanol; EGF: Epidermal growth factor; RA: Retinoic acid; M-CSF: Macrophage colony-stimulating factor; IL-3: Interleukin-3; IL-7: Interleukin-7; TPO: Thrombopoietin; SCF: Stem cell factor; AFP: Alpha-fetoprotein; CK18: Cytokeratin 18; HNF4: Hepatocyte nuclear factor 4; CYP3A4: Cytochrome P450 3A4; CYP7A1: Cytochrome P450 7A1; CK8: Cytokeratin 8; CK19: Cytokeratin 19; PEPCK: Phosphoenolpyruvate carboxykinase; HNF4α: Hepatocyte nuclear factor 4 alpha; HNF6: Hepatocyte nuclear factor 6; CEBPα: CCAAT/enhancer binding protein alpha; AAT: Alpha-1-antitrypsin; HNF4A: Hepatocyte nuclear factor 4 alpha; CYP3A5: Cytochrome P450 3A5; CYP2B6: Cytochrome P450 2B6; HGD: Homogentisate 1,2-dioxygenase; PDGFRβ: Platelet-derived growth factor receptor beta; PCDH7: Protocadherin 7; COL1α1: Collagen type I alpha 1 chain; DES: Desmin; P75NTR: P75 neurotrophin receptor; ALCAM: Activated leukocyte cell adhesion molecule; ACTA2: Actin alpha 2, smooth muscle; LRAT: Lecithin retinol acyltransferase; RELN: Reelin; NCAM1: Neural cell adhesion molecule 1; PECAM1: Platelet endothelial cell adhesion molecule 1; VWF: Von willebrand factor; LYVE1: Lymphatic vessel endothelial hyaluronan receptor 1; FCGR2B: Fc gamma receptor IIb; STAB1: Stabilin 1; FVIII: Factor VIII; STAB2: Stabilin 2; CLEC1B: C-type lectin domain family 1 member B; RAMP3: Receptor activity-modifying protein 3; CFTR: Cystic fibrosis transmembrane conductance regulator; TRPV4: Transient receptor potential vanilloid 4; PKD1: Polycystin 1; PKD2: Polycystin 2; SSTR2: Somatostatin receptor; ALP: Alkaline phosphatase; KRT7: Keratin 7; SOX9: SRY-box transcription factor 9; IL-6: Interleukin-6; CSF1: Colony-stimulating factor 1; HLA-DRB1: Human leukocyte antigen-DRB1; IL-1β: Interleukin-1 beta; MARCO: Macrophage receptor with collagenous structure; TIMD4: T-cell immunoglobulin and mucin domain-containing protein 4; VCAM1: Vascular cell adhesion molecule 1; CPVL: Carboxypeptidase, vitellogenic-like; VSIG4: V-set and immunoglobulin domain-containing protein 4; FOLR2: Folate receptor 2.