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

Figure 1 Illustration of the constituents for human pluripotent stem cells differentiation towards liver lineages. The image shows the constituents for major liver lineage generation from stem cells, including medium, the supplements and cytokine cocktails, and lineage-specific biomarkers. HSCs: Hepatic stellate cells; LSECs: Liver sinusoidal endothelial cells; DMEM: Dulbecco’s modified eagle medium; MARCO: Macrophage receptor with collagenous structure; VCAM1: Vascular cell adhesion molecule 1; bFGF: Basic fibroblast growth factor; TPO: Thrombopoietin; BMP4: Bone morphogenetic protein 4; ALB: Albumin; AFP: Alpha-fetoprotein; CFTR: Cystic fibrosis transmembrane conductance regulator; SSTR2: Somatostatin receptor 2; KRT7: Keratin 7; SOX9: SRY-box transcription factor 9; HGF: Hepatocyte growth factor; MTG: Methyl-β-cyclodextrin; EGF: Epidermal growth factor; LYVE1: Lymphatic vessel endothelial hyaluronan receptor 1; VEGF-A: Vascular endothelial growth factor A; ITS: Insulin-transferrin-selenium; PDGFRβ: Platelet-derived growth factor receptor β; FGF1: Fibroblast growth factor 1; DEX: Dexamethasone; KGF: Keratinocyte growth factor; ATRA: All-trans retinoic acid; FGF4: Fibroblast growth factor 4; IL: Interleukin; M-CSF: Macrophage colony-stimulating factor.

Figure 2 Stem cell-based liver organoids. Illustration image shows the major subtypes of stem cell-based liver organoids and the corresponding biomarkers. ALB: Albumin; HNF4A: Hepatocyte nuclear factor 4 alpha; HNF1B: Hepatocyte nuclear factor 1 beta; KRT7: Keratin 7; KRT19: Keratin 19; AFP: Alpha-fetoprotein; A1AT: Alpha-1-antitrypsin; CEBPA: CCAAT/enhancer binding protein alpha; CYP: Cytochrome P450; CK7: Cytokeratin 7; STAB2: Stabilin 2; LYVE1: Lymphatic vessel endothelial hyaluronan receptor 1; CK18: Cytokeratin 18; FCGR2B: Fc gamma receptor IIb; ADRA1B: Alpha-1B adrenergic receptor; TBX3: T-box transcription factor 3; WT1: Wilms tumor 1; ASGR1: Asialoglycoprotein receptor 1; ASGR2: Asialoglycoprotein receptor 2; SERPINA1: Serpin family a member 1; TTR: Transthyretin; TDO2: Tryptophan 2,3-dioxygenase; COL1A1: Collagen type I alpha 1 chain; TIMP1: Tissue inhibitor of metalloproteinases 1; KRT17: Keratin 17; TACSTD2: Tumor-associated calcium signal transducer 2.

Figure 3 Organoid-based clinical trials for liver diseases. A: The categories of the registered liver organoid-based clinical trials according to ClinicalTrial.gov; B and C: The status and location of the abovementioned liver organoid-based clinical trials; D: The distribution of the organoid-based clinical trials for liver diseases according to clinical trial number [condition (N11)] and the corresponding enrolled participants [enrollment (Log₁₀N12)]. HCC: Hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis.

Figure 4 Stem cell-based clinical trials for liver diseases. A: The categories of the registered stem cell-based clinical trials for liver diseases according to ClinicalTrial.gov; B-D: The status, clinical stage and location of the abovementioned stem cell-based clinical trials; E and F: The distribution of stem cell-based clinical trials for liver diseases according to the enrolled participants [enrollment (Log₂N21)] and the corresponding cell types (N22) or the clinical trial number [condition (N23)]. BM-EPCs: Bone marrow-derived endothelial progenitor cells; LC: Liver cells; MSCs: Mesenchymal stem/stromal cells; hiPSCs: Human induced pluripotent stem cells; BM-MSCs: Bone marrow-derived mesenchymal stem/stromal cells; UC-MSCs: Umbilical cord-derived mesenchymal stem/stromal cells; ACLF: Acute-on-chronic liver failure; NASH: Non-alcoholic steatohepatitis.