Review Article

The Efficiency of Stem Cells (SCs) Differentiation into Functional Hepatocytes for Treating Liver Disorders: A Systematic Review

Table 1

Overview of in vitro differentiation efficacy of SCs into hepatocytes.

Cell sourceIntervention (s)OutcomeAuthor (year)

MSCsCultured in biomicrofluidic cell culture deviceInduced hepatic differentiation of SCs efficiently with significantly higher urea production[30]
MSCsCocultured with AML12 hepatocytes2-fold increase in ALB expression
2.5-fold increase in CK-18 expression
[8]
MSCsTreated with valproic acid and cultured on 3D collagen scaffoldVPA-treatment cells within the 3D collagen scaffold significantly enhanced glycogen storage. Also, expression of hepatic genes: CK-18, AFP, and proteins: AFP and ALB.[19]
BMSCsCultured with murine fetal liver cells (FLCs) and HGF in laminin coated dishesDifferentiated cells expressed ALB, AFP, and CK-19[13]
BMSCsSequential differentiation protocolMore pronounced differentiation of SCs into functional hepatocytes[32]
BMSCsCultured with liver tissue homogenateProduced hepatocyte-like morphological characteristics, AFP expression, increasing of both urea, and ALB levels[28]
BMSCsTreated with DLL4Restored damaged liver by enhancing cholangiocyte differentiation from BMSCs[25]
BMMSCs or UMSCsTreated with HGF and oncostatin MProduced ALB, glycogen storage, urea secretion, uptake of LDL, and phenobarbital-inducible cytochrome P450 activity
Generated functional hepatocytes
[23]
BMMSCsCocultured with liver cellsStrongly expressed ALB, AFP, and CK-18 in mRNA and protein level[29]
BMMSCsCocultured with liver extractExpressed hepatic specific marker genes including AFP, CK-18, and HNFa
Differentiated cells were able to detoxify ammonia into urea, store glycogen, and synthesize glucose
[27]
BMMSCsIndirect coculture systemEnhanced the differentiation efficacy of SCs, upregulation of hepatic-specific markers (ALB, and AFP), enhanced glycogen storage, and improved LDL uptake[36]
BMMSCsCCl4 induced liver injured mice serumMarked increase in hepatic characteristics: High level of glycogen storage and urea production, expression of hepatic markers (ALB, CK-8, CK-18, and CK-19).[51]
HSCsCocultured with injured liver cellsExpression of CK-18, HNF4, ALB, and CK-19[42]
WJMSCsInjured hepatocyte cocultured with WJMSCs pretreated with Vit EReduced ALT, ALP, and mRNA level of Cyp2e1, Hif1-α, and IL-1β to normal level[14]
LSCsCocultured with hepatic stellate cellsEnhanced the functional differentiation into mature hepatic cells[5]
PMSCsCultured with liver cells on 3D scaffoldIncreased secretion of ALB and urea increased activity of CYP 1A2, CYP1A2, and CYP3A4,[4]
PDSCsTreated with GinsenosidesExpressed several hepatocyte specific markers: HNF1α, HNF4α, and ALB
Greater hepatogenic differentiation
[20]
MaGSCsCocultured with stromal cellsGenerated high numbers of mature and functional hepatocytes[12]
PSCsCultured on human liver progenitor HepaRG-derived acellular matrix (ACM)Promoted further hepatic differentiation of PSCs into hepatocytes[26]
hPSCsUse of tank bioreactor with 150 ml working volume of physiological oxygen concentrationsGenerated functional hepatocytes, which expressing liver-specific marker gene[37]
MenSCsCocultured with stellate cellsIncreasing in ALB and CK-18 expression[9]
ASCsCombination of HGF, Dex, and OSM in the presence or absence of IGF-IIGF-I generated more functional hepatocyte-like cells[22]
FLCsCultured on 3D scaffoldSignificantly induced hepatic cells differentiation[15]
AECsTreated with synthesized isorhamnetinALB was upregulated. Increasing in CYP enzyme mRNA levels, ICG uptake and release, glycogen storage activity, and urea secretion[18]
ESCsActivin AFGF-4BMP-2The differentiated cells exhibit characteristics of mature hepatocytes[21]
ESCsCocultured with mesoderm-derived cell line (M15) and FGFCould induce efficient differentiation[11]
ESCsLentiviral vector, containing the fetoprotein promoter driving enhanced green fluorescent protein expression (AFP:eGFP)Generated mature hepatocytes[53]
ESCsCocultured with hepatic cells (HepG2)Increased in the expression of liver genes: ALB, AFP, and G6P
Enhanced efficient of SCs differentiation
[10]
ESCsStepwise cell differentiation protocolProduced functional hepatocytes expressing: CK8, CK18, CK19, AFP, and ALB[47]
ESCsMembrane substratum stably expressing laminin-511Expressing mature hepatocyte markers and secretion of a high levels of albumin[17]
ESCsCultured on 3D scaffoldUpregulated hepatic gene expression, ammonia metabolism activity, ALB production, increasing in drug-induced cytochrome P450 gene expression.
Induction of more functional maturation in hESC-derived hepatic cells
[6]
ESCsActivin A, FGF-2; FGF-4, BMP2, FGF-10, HGF 4, and EGFProduced viable cells with hepatocyte morphology, expression of alpha-antitrypsin, CK-8 and LDL receptor, producing ALB and ALT[54]
ESCsCultured with calcium silicate extractsPromote hepatic differentiation of human ESCs[24]
ELCsCultured on biodegradable and polymeric membranesPromoted expansion and functional differentiation of ELCs into hepatocytes[7]
ESCs line (ORMES-6)Cultured in optimal culture conditionProduced hepatocyte-like cells that expressed ALB, AFP, HNF 3, G6-P, and cytochrome P450 genes and proteins[34]
iPScStepwise protocolCould efficiently differentiate SCs into hepatocytes[33]
iPSCsTwo-step protocolEfficiently generated highly matured hepatocytes[35]
iPSCsCultured on matrigelProduced functional hepatocytes[50]
iPSCsHepatic differentiation mediaIt could efficiently generate functional hepatocytes[55]
iPSCsDriving of mir122 (a liver specific microRNA)Shortened the differentiation time[48]
PSCsSix consecutive differentiation steps protocolHepatocyte-like cells that express characteristic hepatocyte enzymes[31]

MSC: Mesenchymal stem cell, VPA: Valproic acid, CK: Cytokeratin, AFP: Alfa Phyto protein, ALB: Albumin, BMSC: Bone mesenchymal stem cell, HGF: Hepatocyte growth factor, DDL4: Delta like ligand, BMMSC: Bone marrow mesenchymal stem cell, UMSC: Umbilical mesenchymal stem cell, WJMSC: Warton Jelly mesenchymal stem cell, LDL: Low density lipoprotein, HNF: Hepatocyte nuclear factor, HSC: Hematopoietic stem cell, CCL4: Carbon tetrachloride, LSC: Liver stem cell, PMSC: Placenta mesenchymal stem cell, PDSC: Placenta-derived stem cell, MaGSC: Germ line-derived multipotent adult stem cell, MenSC: Menstrual stem cell, IGF: Insulin like growth factor, FLC: Fetal liver progenitor cell, AEC: Amnion epithelial cell, ESC: Embryonic stem cell, FGF: Fibroblast growth factor, G6P: Glucose 6 phosphate, ALT: Alanine transferase, EGF: Epidermal growth factor, ELC: Embryonic liver cell, iPSC: induced pluripotent stem cell, HSL: Liver epithelial cell line, IL-1β: Interleukin 1β, Cyp2e1: Cytochrome 450 2E1.