Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

Table 1 Mesenchymal stem/stromal cells clinical trials for liver diseases

Ref.	Etiology or disease	Cell source/origen	Study design (n; groups)	Cell administration condition			Phase	Results	Follow up	Side effects
				Dose	P value	Route
Mohamadnejad et al[14] 2007	Cirrhosis	BM/Auto	n = 4	1, 0.6 × 107	2-4	IV	I	MELD ↓	12 mo	None
Kharaziha et al[15] 2009	Cirrhosis	BM/Auto	n = 8; 4 HBV 1 HCV 1 Alcohol 2 Control	3.5 × 107	3-4	PV/IV	I/II	MELD ↓	24 wk	None
El-Ansary et al[16] 2010	Cirrhosis	BM/Auto	n = 12	10 × 106	1	IS/IV	I	MELD ↓; no differences between IS vs IV	6 mo	NA
Peng et al[29] 2011	Cirrhosis (HBV)	BM/Auto	n = 158; 53 MSC 105 Control	3.4-3.8 × 108	3	HA	I/II	ALB ↑, MELD ↓	48 mo	None
Amer et al[34] 2011	Cirrhosis (HCV)	BM/Auto	n = 40; 20 MSC 20 Control	2 × 107	NA	IS/IH	I/II	ALB ↑, C.P ↓, MELD ↓	6 mo	Fever (50%), transient shivering (15%)
El-Ansary et al[17] 2012	Cirrhosis (HCV)	BM/Auto	n = 25; 9 MSC 6 Hep. Diff. 10 Control	1 × 106/kg MSC or 40% HLCs and 60% MSCs	5	IV	II	ALB↑, MELD ↓, no differences between HLCs vs MSCs.	6 mo	NA
Zhang et al[18] 2012	Cirrhosis (HBV)	UC/Allo	n = 45; 30 MSC 15 Control	0.5 × 106/kg every 4 wk, 3 times	3-4	IV	I/II	ALB ↑, MELD↓, ascites ↓	48 wk	None
Shi et al[19] 2012	Acute-on-chronic Liver failure (HBV cirrhosis)	UC/Allo	n = 43; 34 MSC 9 Control	0.5 × 106/kg every 4 wk, 3 times	3-4	IV	I/II	ALB ↑, PT ↑, MELD ↓, SR↑	72 wk	None
Mohamadnejad et al[20] 2013	Cirrhosis	BM/Auto	n = 25; 14 MSC 11 Control	2 × 108	3-4	IV	II	No beneficial effect	12 mo	None
Wang et al[21] 2013	UDCA-resistant PBC	UC/Allo	n = 7	0.5 × 106/kg every 4 wk, 3 times	4	IV	I/II	ALP↓, γ-GT ↓, quality of life↑ (fatigue↓, pruritus↓)	48 wk	None
Amin et al[35] 2013	Cirrhosis	BM/Auto	n = 20	10 × 106	2	IS	I/II	ALT ↓,AST ↓,BIL ↓, PT ↓, ALB↑, PT↑	24 wk	None
Jang et al[30] 2014	Cirrhosis	BM/Auto	n = 11	5 × 107 every 4 wk, 2 times	4-5	HA	II	C.P ↓, TGF-β ↓, αSMA ↓, collagen1 ↓, fibrosis ↓,	20 wk	None
Wang et al[18] 2014	UDCA-resistant PBC	BM/Allo	n = 10	3-5 × 105/kg	3-5	IV	I/II	ALT ↓, AST ↓, γGT, BIL ↓, IgM ↓, Tregs ↑, IL-10↑, CD8+T cells↓	12 mo	None
Salama et al[23] 2014	Cirrhosis	BM/Auto	n = 40; 20 MSC 20 Control	1 × 106/kg	0	IV	II	ALT↓, AST↓,BIL↓, ALB↑, PT↑, C.P↓, ascites ↓	26 wk	NA
Xu et al[31] 2014	Cirrhosis	BM/Auto	n = 56; 27 MSC 29 Control	0.75 × 106/kg	NA	HA	II/III	ALB↑, MELD↓, ↑ Tregs/Th17 cell ratio, IL-17↓, TNFα↓, IL-6↓, TGF-β ↑	24 wk	NA
Suk et al[32] 2016	Cirrhosis	BM/Auto	n = 55; 18 MSC (× 1 d) 19 MSC (× 2 d) 18 Control	5 × 107 (1 mo post BM asp.) /5 × 107 (1 and 2 m post BM asp.)	4-5	HA	II	C.P ↓, fibrosis ↓	12 mo	None
Zhang et al[24] 2017	Ischemic-type biliary lesions	UC/Allo	n = 82; 12 MSC 70 Control	1 × 106/kg; week 1, 2, 4, 8, 12 and 16	4	IV	II/III	BIL↓,ALP↓, γGT ↓, graft survival ↑	24 mo	None
Detry et al[25] 2017	Liver transplantation	BM/Allo	n = 20; 10 MSC 10 Control	1.5-3 × 106/kg; day 3 post-transplant	2-3	IV	I/II	No beneficial effect	6 mo	None
Sakai et al[33] 2017	Cirrhosis	AT/Auto	n = 4	6.6 × 105/kg	0	HA	I	ALB ↑, PT↓	1 mo	None
Shi et al[26] 2017	Liver transplantation	UC/Allo	n = 20; 14 MSC 13 Control	1 × 106/kg; every 4 wk, 3 times	3-4	IV	I	ALT↓, AST↓, BIL ↓, improve liver allograft histology, acute rejection↓ (↑ peripheral Tregs, ↑ Tregs/Th17 cell ratio).	12 wk	None
Hartleif et al[27] 2017	Pediatric liver transplantation	BM/Allo	n = 7	1 × 106/kg; day 0 and day 2 post-transplantation	2-3	PV/IV	I	NA	24 mo	None
Lin et al[28] 2017	Acute-on-chronic Cirrhosis (HBV)	BM/Allo	n = 110; 56 MSC 54 Control	1-10 × 105 cells/kg; 1/wk, 4 wk	5-6	IV	I/II	MELD↓, SR↑, infections↓	24 wk	None

P: Passage; BM: Bone Marrow; Allo: Allogeneic; Auto: Autologous; IV: Intravenous Infusion; MELD: Model for end-stage Liver Disease; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; IS: Intrasplenic; IH: Intrahepatic; NA: Not available; HA: Hepatic artery; CP: Child-Pugh score; HLC: Hepatocyte-like cells; UC: Umbilical cord; SR: Survival rate; Cr: Creatinine; BIL: Bilirubin; PBC: Primary biliary cirrhosis; UDCA: Ursodeoxycholic acid; Hep. Diff.: Hepatocyte differentiated; PT: Prothrombin time; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; γ-GT: γ-glutamyltranspeptidase; Asp: Aspiration.