Stem cell-based regenerative opportunities for the liver: State of the art and beyond

Table 1 Clinical trials using stem cells for the treatment of liver diseases

Ref.	Cell Source	No. of patients/administration route	Disease cause	No. of cells infused	Follow-up period	Outcomes
29	Fetal liver-SCs (EpCAM+)	25: hepatic artery	End-stage liver cirrhosis	80 × 106	6 mo	Improved liver function and MELD score
30	Fetal liver-SCs (EpCAM+)	2: hepatic artery	Advanced cirrhosis	42 × 106 and 60 × 106	12 mo	Biochemical and clinical improvement
133	BM-MSCs	4: peripheral vein	Decompensated liver cirrhosis	31.73 × 106	12 mo	Well tolerated and safe procedure; improved liver function
134	MSCs from iliac crest	8: peripheral or portal vein	End-stage liver disease	30 × 106-50 × 106	24 wk	No adverse effects; improved MELD and liver function
135	BM-MSCs stimulated to hepatic lineage	20: control 10: intrasplenic 10: intrahepatic	post-HCV end-stage liver disease	2 × 107 in a total of 2 × 108 MNCs	6 mo	Improved ascites, MELD and CP score; no difference between intrahepatic and intrasplenic groups
136	BM-MSCs	105: control 53: treated/hepatic artery	post-HBV liver failure	3.4 × 108-3.8 × 108	192 wk	No serious side effects or complications; improved ALB, TBIL, PT and MELD score
137	Differentiated BM-MSCs vs undifferentiated	10: control 15: treated/intravenous	post-HCV liver cirrhosis	1 × 106/kg body weight	6 mo	Improved MELD score, BIL, ALB and PC
138	BM-MSCs	20: intrasplenic	post-HCV liver cirrhosis	10 × 106	6 mo	Decreased TBIL, AST, ALT, PT; improved ALB, PC, PT, INR
139	BM-MSCs	11: hepatic artery	Alcoholic cirrhosis	5 × 107 injected twice	12 mo	No significant side effects; histological improvement; improved CP score
140	UC-MSC	15: control 30: treated/intravenous	post-HBV decompensated liver cirrhosis	0.5 × 106/kg body weight	1 yr	No significant side effects; improved liver function and MELD score; reduced ascites
141	UC-MSC	19: control 24: treated/intravenous	post-HBV acute-on-chronic liver failure	0.5 × 106/kg body weight	72 wk	No significant side effects; improved liver function and MELD score; increased survival
142	UC-MSC	7: peripheral vein	Primary biliary cirrhosis	0.5 × 106/kg	48 wk	No obvious side-effects; decreased serum ALP and GGT
143	Autologous MSCs	12: control 15: treated/peripheral vein	Decompensated cirrhosis	195 × 103	12 mo	No beneficial effect
166	BM-MNCs	9: peripheral vein	Liver cirrhosis	5.20 +/- 0.63 × 109 MNCs	24 wk	No major adverse effects; improved ALB, CP scores
175	G-CSF mobilization	40: controls 8: treated/subcutaneous	Severe liver cirrhosis	G-CSF: 5 μg/kg every 12 h for 3 d	8 mo	No adverse events; improved MELD score
176	Autologous G-CSF mobilized CD34+ cells	2: peripheral vein	End-stage liver disease	G-CSF :10 μg/kg per day: 4-5 d/CD34+ cells: 2.31 × 106/kg and 4 × 106/kg	30 to 34 mo	Safe and well tolerated procedure; improved CP and MELD scores
177	Autologous G-CSF-mobilized CD34+ cells	3: portal vein 2: hepatic artery	Liver insufficiency	CD34+ cells: 1 × 106 to 2 × 108	60 d	No complications or specific side effects; improved ALB
178	G-CSF mobilization	11: control 13: treated/subcutaneous	Alcoholic cirrhosis	G-CSF: 10 μg/kg per day 2 times daily for 5 d	12 wk	Effective CD34+ cells mobilization; increased HGF; induced HPC proliferation
179	G-CSF mobilization	24: control 23: treated/subcutaneous	Acute-on-chronic liver failure	G-CSF: 5 μg/kg for 12 doses	60 d	Increased survival; reduced CTP, MELD and SOFA scores
180	G-CSF mobilization	23: control 23: treated/subcutaneous	Severe alcoholic hepatitis	G-CSF: 5 μg/kg every 12 h for 5 d	3 mo	Safe and effective HSCs mobilization; improved liver function and survival
181	Experimental PA-PE, combined with G-CSF	1: subcutaneous	Acute-on-chronic liver failure	10 μg/kg per day for 5 d	2 mo	Rapid and long lasting clinical improvement; HSCs mobilization and a ductular reaction
182	G-CSF mobilization	24: subcutaneous	Acute on chronic liver failure	G-CSF: 5 and 15 μg/kg per day for 6 d		Safety and feasibility of G-CSF mobilization; no clinical/biochemical improvement
183	G-CSF mobilization	18: subcutaneous	Liver cirrhosis	increasing doses of G-CSF daily for 7 d	3 wk	No severe adverse events; no liver function significant modification
184	Autologous G-CSF mobilized CD34+ cells	1: portal vein	Drug-induced hepatitis	G-CSF: 15 μg/kg/for 5 d CD34+ cells: 5 × 106	30 d	Improved liver function; wide areas of regeneration in liver biopsy
185	Autologous G-CSF-mobilized CD34+ SCs	2: hepatic artery 3: portal vein	Chronic liver disease	G-CSF: 526 μg/d: 5 d, CD34+ cells: 1 × 106-2 × 108	6-18 mo	No side effects; improved BIL and ALB
186	Autologous G-CSF-mobilized cultured CD34+ SCs	9: hepatic artery	Alcoholic liver cirrhosis	520 μg/d: 5 d/mean TNCC:229.7 × 106	12 wk	No side effects; improved BIL, ALT, AST, CP score and ascites
187	PBMCs from G-CSF mobilized PB	20: control 20: treated	Decompensated liver cirrhosis	5-10 μg/kg per day for 4 d. PBMC: 107-108/kg	6 mo	No major adverse effects; improved liver function

G-CSF: Granulocyte-colony-stimulating factor; TBIL: Total bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; CP: Child-Pugh; BM: Bone marrow; UC: Umbilical cord; HSC: Hematopoietic stem cell; HGF: Hepatocyte growth factor; EpCAM: Epithelial cell adhesion molecule; MSCs: Mesenchymal stromal cells; HCV: Hepatitis C virus; PT: Prothrombin time; ALB; Albumin; PC: Platelet count; INR: International normalized ratio; PA-PE: Experimental plasmapheresis with plasma-exchange; MELD: Model for End-stage Liver Diseases; ALP: Alkaline phosphatase; GGT: γ-glutamyl transferase; UC-MSC: Umbilical cord blood-mesenchymal stromal cells; BM-MSCs: Bone marrow-mesenchymal stromal cells.