Table 1.

Summary of Clinical Trials on Cell Therapy in Patients With Liver Cirrhosis.

Authors and journal	N	Type of study	Indication	Type of Cell therapy	Dose and route	Outcome
Hepatocyte cell transplantation
Mito M et al, Cell Transplantation.126 1993	10	Observational, Hepatocyte transplantation in man.	Liver cirrhosis	Hepatocytes	Intraportal	Upto 11 month survival in one patient
Skvorak et al.127 Mol Ther. 2009	Mice study	Open level experimental	Maple Syrup Urine Disease	Hepatocytes	Direct into liver
Kobayashi et al. Cell Transplant. 2000	Mice study	Experimental open level	Chronic Liver Failure	Hepatocytes	Spleen
Trials of unsorted Bone Marrow–Derived Mononuclear Cell Transplant in Liver Disease
Saito et al, Stem Cell Dev,128 2011	5:Treatment 5:Controls	RCT	Alcoholic Cirrhosis	BM-MNC	Single dose, peripheral vein	Improved CTP scores and INR, higher serum albumin, and total protein
Lyra et al, Eur Jou of Gastr Hepatol,77 2010	15: Treatment 15: Controls	RCT	Decompensated cirrhosis on waiting list for LT	BM-MNC	Single dose, hepatic artery	Improved serum albumin and CP score up to 90days
Spahr et al,129 PLoS One 2013	28: Treatment 30:Controls	RCT	Decompensated cirrhosis, mean MELD score-19	BM-MNC + GC-CSF	Single dose, hepatic artery	No significant differences between study groups
Trials of Sorted Hematopoietic Stem Cell Transplant in Liver Disease
Gordan et al,81 Stem Cell 2006	5	Phase 1 open Uncontrolled trial	Decompensated cirrhosis (Ethanol-4, HCV-1)	CD34+	Single dose, portal vein or hepatic artery	Serum albumin and T Bil improved
Spahr L et al,130 Hepatology. 2008	11: control 13: treated	RCT	Alcoholic cirrhosis	CD 34+	10 μg/kg/day Subcutaneous G-CSF for 5 days.	Effective CD34+ cells mobilization; increased Hepatocyte Growth Factors
Levicar et al,82 Cell Prolif 2008	5	Uncontrolled trial	Cirrhosis	CD34+	Single dose, hepatic artery	Improved T Bil and CP up to 12 months, no short- and long-term side effects
Trials of G-CSF–Mobilized Hematopoietic Stem Cell Transplant in Patients with Liver Disease
Han Y et al. Cyto-therapy,131 2008	20: control 20: treated	Phase 2 open RCT	Decompensated cirrhosis	PBMCs from G- CSF mobilized PB	Single dose, hepatic artery Vs. peripheral vein for 4 days for HSC mobilization	GC-SF plus PBMNC group had better liver test results up to 6 month follow up, no major adverse effects
Shasthry SM et al,86 Hepatology. 2019	14:Treatment 14:Placebo	RCT	Steroid Non responsive Severe Alcoholic Hepatitis	G-CSF	Multiple doses Subcutaneous	Decrease in MELD, and Maddrey’s discriminant function, Infections and decreased 90-day mortality in the G-CSF arm
Kedarisetty CK et al.88 Gastro 2015	29:Treatment 26:Placebo	Double blinded RCT	Decompensated cirrhosis	G-CSF+ Darbopoietin α	Multiple doses, Subcutaneous 4 weeks	Improved CTP, MELD and survival at 12 month. Decreased sepsis
Newsome PN et al.90 Lancet Gastroenterol Hepatol. 2018	27: standard care 26: G-CSF 28: G-CSF plus stem-cell infusion	Multicentre, open-label, randomized, controlled phase 2 trial	Compensated liver cirrhosis and MELD scores of 11–15·5	G-CSF alone or G-CSF plus stem-cell infusion	G-CSF (lenograstim) at 15 μg/kg bodyweight daily for 5 consecutive days.	No significant changes in MELD score More ascites and encephalopathy in G-CSF group.
Philips CA.91 J Clin Exp Hepatol. 2019	56: GCSF, per-protocol analysis 24: Matched historical controls	Retrospective study	Decompensated cirrhosis	G-CSF (5 μg/kg daily 5 days and every 3rd day thereafter until day 26)	Multiple doses Peripheral vein	Compared to a matched HC group, patients receiving GCSF had higher mortality (75% vs 46%, P = 0.04) at one year.
De A.89 Clin Gastroenterol Hepatol. 2020	50: standard care 50: G-CSF	Open-label trial	Decompensated cirrhosis	5 days of G-CSF every 3 months	Multiple doses Peripheral vein	GCSF- Significantly more CD34+ cells on day 6 than on day 0 (P < 0.001) Significant reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased ascites control, fewer infections and hospitalizations, lower liver stiffness measurements, and increased quality of life
Trials of G-CSF–Mobilized Hematopoietic Stem Cell Transplant in Patients with ACLF
Garg et al.118 Gastro 2012	23: Treatment 24:Placebo	Double blinded RCT	ACLF (APASL)	G-CSF	Multiple doses Peripheral vein	Improved MELD score, better patient survival Less sepsis, HRS and HE
Duan XZ87 et al. WJG 2013	27:Treatment 28:Placebo	RCT	HBV related ACLF	G-CSF	Multiple doses Peripheral vein	Increased CD34 (+) cell mobilization, improved the liver function and survival rate.
Singh V119 et al Am Jour Gastroenterol 2014	23:Treatment 23:Placebo	Open RCT	Severe Alcoholic hepatitis	G-CSF	Multiple doses Peripheral vein	Increased CD34 (+) cell mobilization, CTP, MELD, mDF score, and survival rate.
Engelmann C et al.92 J Hepatol 2021	88: Treatment 88: SMT	Open-label, Plase 2 RCT	ACLF defined by EASL-CLIF criteria	G-CSF (5 μg/kg daily 5 days and every 3rd day thereafter until day 26)	Multiple doses Peripheral vein	No improvement in overall and transplant free 90 and 360 day survival. No prevention of infection.
Trials of Mesenchymal Stem Cell Transplant in Liver Disease
Peng et al,97 Hepatology 2011	53: Treatment 105: Controls	Phase 2, open, RCT	HBV Related Cirrhosis-Decompensated	BM-MSC	Single dose infusion, hepatic artery	No mortality benefit. Decreased Bilirubin, improved INR and MELD score. No complications
Amin MA et al, Clinical Transplantation.120 2013	20	Open level, Uncontrolled trial, for safety	Post HCV child C liver cirrhosis	bone marrow derived mesenchymal stem cells	Intrasplenic injection	Decreased Bilirubin, AST, ALT, PT; improved Albumin, and INR
Mohamadnejad et al.96 Liv Int 2013	15:Treatment 12: Placebo	RCT	Decompensated cirrhosis MELD >15	BM-MSC	Single dose, peripheral vein	No differences between the groups
Liang J et al, International Journal of Rheumatic Diseases. 2017	26	Open level, uncontrolled	Cirrhosis related to Autoimmune liver diseases	Allogeneic MSCs	Peripheral vein	improved MELD and liver function, without any side effect
El-Ansary et al.121 Stem cell rev 2012	15:Treatment, and 10:Controls	Phase 2, open, Uncontrolled trial	HCV-related cirrhosis and MELD score >12	BM-MSC	Single dose, Peripheral vein	Decreased Bilirubin, improved INR, albumin, and MELD score
Trials of Mesenchymal Stem Cell Transplant in Patients with ACLF
Shi M et al. Stem Cells Transl Med,122 2012	24:Treatment 19: Placebo	open-labeled and controlled	HBV related ACLF	UC-MSC	three times at 4-week intervals, Peripheral vein	Increase 90 day survival, reduced the MELD scores; increased serum albumin, and platelet counts
Li YH et al. Stem Cell Rev Rep,123 2016	11:PE + MSC 34:Only PE	Prospective study, open-labeled	HBV related ACLF	UC-MSC	Single doses, Peripheral vein	Improves the hepatic function and survival
Lin BL et al124 Hepatology 2017	56:Treatment 54:Placebo	open-label, RCT	HBV related ACLF	Allogeneic BM-MSC	weekly for 4 weeks, Peripheral vein	Improved survival and liver function tests, Decrease incidence of Sepsis and multiorgan failure
Macrophage therapy
Thomas JA et al,104 Hepatology. 2011	Experiential mice study	Mice study	Liver Cirrhosis	Macrophages	Single dose treatment	Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function.
Bird TG et al, Proc Natl Acad Sci U S A.125 2013	Experimental mice study	Mice study	Liver cirrhosis	Macrophage	Single dose treatment, intravascular	Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.