Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
Yong-Hong Wang , En-Qiang Chen
Correspondence to: En-Qiang Chen
ORCID https://orcid.org/0000-0002-8523-1689
E-mail chenenqiang1983@hotmail.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver.
Published online February 27, 2023
Copyright © Gut and Liver.
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
Keywords: Acute liver failure, Mesenchymal stem cells, Hepatocyte-like cells, Immunomodulation
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. The first step in treating ALF is to remove the cause, such as alcohol withdrawal, anti-hepatitis virus, and discontinuation of liver-damaging drugs.1 The main treatments for ALF include conventional medical treatment, artificial liver support systems, and liver transplantation. Liver transplantation is the most effective treatment, but the lack of donor's livers and the high cost of transplantation limit its broad application.2,3 In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Meanwhile, stem cells are helpful in the treatment of many diseases, including liver failure, liver fibrosis, graft versus host disease, type 2 diabetes, etc.4-6
Stem cells are a kind of cells with self-replication, high proliferation, and multi-differentiation potential, which can exert therapeutic effects in various ways such as immunomodulation and tissue repair.7,8 Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their vast sources, low immunogenicity, and no ethical restrictions.9 Previous studies have shown that MSCs treat ALF by differentiating into hepatocyte-like cells (HLCs), regulating immune cells, and secreting therapeutic factors.10-12 Although MSCs are effective in treating ALF, the application of MSCs in ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSCs transplantation.
MSCs may differentiate into HLCs for tissue repair during the treatment of ALF. The induction method of stem cell-derived HLCs is phased induction by using cytokines.13-15 First, the MSCs were cultured in serum-free pretreatment medium (Iscove’s Modified Dulbecco’s Medium [IMDM]+20 ng/mL epidermal growth factor+10 ng/mL basic fibroblast growth factor [bFGF]) for 2 days. Then, the MSCs were cultured in differentiation inducing medium (IMDM+20 ng/mL hepatocyte growth factor [HGF]+10 ng/mL bFGF+nicotinamide 0.61 g/L) for 7 days. Finally, the MSCs were cultured in the maturation medium (IMDM+20 ng/mL oncostatin M+1 μmol/L dexamethasone+50 mg/mL insulin-transferrin-selenium) for 7 to 14 days. Although some scholars have adjusted the differentiation steps of HLCs, the key factors of the classical induction method are still retained.16-18 MSCs can be induced into HLCs
Whether HLCs have better efficacy in ALF than undifferentiated MSCs is uncertain. Wang
The overactivation of the immune system plays an essential role in initiating and accelerating ALF. MSCs can regulate the functions of various immune cells, so many studies have shown that MSCs treat ALF mainly through immune regulation. MSCs improve mitochondrial respiration and monocyte phagocytosis when monocytes are functionally exhausted in acute-on-chronic liver failure (ACLF) mice, thereby reducing liver injury and enhancing liver regeneration.28 However, the excessive activation of monocytes will aggravate ALF, and MSCs therapy can inhibit the activation of monocytes.29 Gazdic
Various substances derived from MSCs have therapeutic effects on ALF, including cytokines, conditioned medium (CM), and exosomes. Previous studies have shown MSC-derived cytokines such as IL-10, IL-4, HGF, PGE2, tumor necrosis factor-inducible gene 6 protein (TSG-6), and heme oxygenase 1 (HO-1) have therapeutic effects on ALF. MSCs can secrete IL-10 to alleviate liver failure, and inhibition of IL-10 secretion can reverse the therapeutic effect of MSCs. IL-10 may treat liver failure by improving mitochondrial damage of hepatocytes.39 Meanwhile, the anti-inflammatory effect of IL-10 may be mediated by STAT3 signaling pathway.40 MSCs attenuate hepatocyte necrosis by secreting HGF. When HGF in MSCs was knocked down, the therapeutic effect of MSCs on acetaminophen (APAP) induced ALF in mice was reduced.41 MSCs can promote the improvement of ALF by inducing hepatocyte proliferation through PGE2. PGE2 increases the expression of PGE4 and enhances the phosphorylation of cAMP response element-binding proteins, leading to the activation of Yes-associated protein (YAP) and the increase of YAP-related gene expression.42 Therefore, cytokines secreted by MSCs can treat ALF by reducing hepatocyte necrosis and promoting hepatocyte proliferation. Moreover, cytokines secreted by MSCs can also act on non-liver parenchymal cells to play a therapeutic role in ALF. Wang
Some studies found that MSC-CM and MSCs have similar therapeutic effects on ALF. MSC-CM is concentrated by ultrafiltration devices to increase the concentration of therapeutic factors. MSC-CM treatment profoundly inhibited hepatocyte death, enhanced liver regeneration, and improved survival in ALF rats.46 In another study, MSCs and MSC-CM exert the therapeutic effect of ALF by stimulating hepatocyte proliferation and inhibiting apoptosis, reducing macrophage infiltration, and transforming the CD4+T lymphocyte into an anti-inflammatory state.47 Parekkadan
In recent years, the application of MSCs-derived exosomes (MSC-Ex) in ALF has received extensive attention. Exosomes, a membranous extracellular vesicle with a diameter of 30 to 150 nm, carry a variety of proteins, nucleic acids, lipids, transcription factors, extracellular matrix proteins, enzymes and receptors, and play a role in treating diseases through these molecules.49 Bone marrow MSC-Ex can reduce hepatocyte oxidative stress
The effectiveness of MSCs in the treatment of ALF has been confirmed, but how to improve its efficacy is worth further study. Studies have reported that editing some target genes of MSCs can enhance the effectiveness of ALF, and the verified target genes include c-Met, C-C motif chemokine receptor 2 (CCR2), C-X-C motif chemokine receptor 4 (CXCR4), hepatocyte nuclear factor 4 alpha (HNF4α), IL-35, HGF, interleukin-1 receptor antagonist (IL-1Ra), forkhead box A2 (Foxa2), and VEGF165, etc. MSCs overexpressing some chemokines (c-Met, CCR2, and CXCR4) are more likely to reach the injured liver and improve the therapeutic effect of ALF.58-61 HNF4α overexpression enhances the therapeutic potential of MSCs in ALF mice by promoting the expression of IL-10 and inducing M2 polarization of macrophages.62 In Con A-induced acute hepatitis mice, MSCs overexpressing IL-35 can reduce the level of interferon gamma (IFN-γ) secreted by liver mononuclear cells through the janus kinase 1 (JAK1)-STAT1/STAT4 signaling pathway.63 Human umbilical cord MSCs overexpressing HGF attenuate liver injury and improve survival rate in ALF mice through anti-apoptosis and anti-oxidation mechanisms.64 In addition, IL-1Ra, an antagonist of IL-1, can promote liver regeneration and inhibit hepatocyte apoptosis after overexpression in MSCs.65 Chae
The pretreatment of MSCs with different stimuli before MSCs transplantation may improve the therapeutic efficacy of ALF. The pretreatment methods used in the experiment include edaravone, IL-1β, tumor necrosis factor-alpha (TNF-α), serum, etc. Edaravone elevating antioxidant levels in MSCs can significantly improve liver tissue repair capacity by increasing MSCs’ homing, promoting proliferation, reducing apoptosis, and increasing the secretion of HGF.68 Nie
Indeed, MSCs combined with other therapies may have better outcomes for ALF than MSCs therapy alone. The menstrual blood MSCs can alleviate liver injury by inhibiting Toll-like receptor 4 (TLR4) mediated PI3K/Akt/mTOR/IkappaB kinase (IKK) signaling pathway. Meanwhile, adenosine A2A receptor (A2AR) agonists can synergize with the menstrual blood MSCs.72 Sang
Some studies on the application and efficacy of MSCs in ALF animal models have been summarized in Table 1 to explore the optimal regimen of MSCs in treating ALF. MSCs have a wide range of tissue sources, including bone marrow, adipose tissue, umbilical cord, placenta, tonsils, etc.77-82 It is unclear whether MSCs from different tissue sources have similar therapeutic effects on ALF. Zare
Table 1. The Application and Therapeutic Effect of MSCs in Animal Models of Acute Liver Failure
MSCs type | Route | Dose (transplant frequency) | Transplant time | Inducer | Animal | Therapeutic effect and mechanism | Reference |
---|---|---|---|---|---|---|---|
hBMSCs | Portal vein | 3×106/kg (1 injection) | Injection immediately after using D-GalN | D-GalN | Pigs | Survival rate↑; inflammation↓; delta-like ligand 4 (DLL4)↑ | 81 |
AT-MSCs | Peripheral vein or splenic vein | 2×106/kg (2 injections) | Injections on day 3 and 8 after using CCL4 | CCL4 | Dogs | Liver enzymes↓; (IL-1, IL-6, IL-8, and IFN-γ)↓; (IL-4 , IL-10, HGF, and VEGFA)↑ | 82 |
BMSCs | Peripheral vein | 1×106/rat (1 injection) | Injections on 12 hr after using TAA | TAA | Rats | Survival rate↑; endotoxin↓; (IL-6 and TNF-α)↓ | 89 |
AT-MSCs | Peripheral vein | 2×105/rat (1 injection) | Injections on 2 hr after using APAP | APAP | Rats | Liver enzymes↓; (TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK)↓; (cyclin D1 and PCNA)↑ | 80 |
hUCMSCs | Peripheral vein | 2×106 or 4×106/rat (1 injection) | Injections on 1 hr after using LPS/D-GalN | LPS/D-GalN | Rats | Liver enzymes↓; (TNF-α, IFN-γ, IL-6, and IL-1β)↓; HGF↑; (Notch, IFN-γ/Stat1, and IL-6/Stat3 )↓ | 78 |
hUCMSCs | Peripheral vein | 5×105/mouse (1 injection) | Injections on 30 min before or after using APAP | APAP | Mice | Liver enzymes↓; (glutathione, superoxide dismutase)↑; (TNF-α and IL-6)↓; HGF↑ | 90 |
T-MSCs | Peripheral vein | 2×106/mouse (1 injection) | Injections on 30 min after using ConA or APAP | ConA or APAP | Mice | Liver enzymes↓; (INF-γ and TNF-α)↓; Galectin-1 is a key effector of T-MSCs | 79 |
hPMSCs | Portal vein or peripheral vein | 1×108/pig (1 injection) | Injections on 18 hr after using D-GalN | D-GalN | Pigs | Liver enzymes↓; (liver inflammation, hepatic denaturation and necrosis)↓; (liver regeneration)↑ | 77 |
MSCs, mesenchymal stem cells; hBMSCs, human bone MSCs; AT-MSCs, adipose tissue MSCs; BMSCs, bone MSCs; hUCMSCs, human umbilical cord MSCs; T-MSCs, tonsil-derived MSCs; hPMSCs, human placenta MSCs; D-GalN, D-galactosamine; CCL4, carbon tetrachloride; TAA, thioacetamide; APAP, acetaminophen; LPS, lipopolysaccharide; ConA, concanavalin A; IL, interleukin; IFN-γ, interferon gamma; HGF, hepatocyte growth factor; VEGFA, vascular endothelial growth factor A; TNF-α, tumor necrosis factor-alpha; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intercellular adhesion molecule-1; PCNA, proliferating cell nuclear antigen; Stat, signal transducer and activator of transcription.
The transplantation routes of MSCs include peripheral vein, portal vein, splenic vein, hepatic artery, intrahepatic injection, intrasplenic injection, etc. MSCs transplanted via tail vein and intrahepatic injection has similar efficacy in liver function and survival rate in ALF rats.85 Putra
The cell dose for MSCs transplantation increases proportionally to body weight in large animals (e.g., dogs and pigs), whereas it is fixed in small animals (e.g., mice and rats) (Table 1). ALF is progressing rapidly, so most studies use single MSCs transplantation, and the transplantation time is as early as possible (Table 1). MSCs transplantation (3×106 cells/kg) immediately after D-galactosamine injection can effectively treat ALF in pigs.81 Moreover, Jiang
Many studies have proved that MSCs can effectively treat ALF in animal models. Similarly, MSCs have therapeutic effects on patients with liver failure in clinical trials. In a randomized controlled trial, Peripheral infusion of allogeneic bone marrow MSCs is safe and effective in HBV-related ACLF patients, and significantly improves the 24-week survival rate by improving liver function and reducing the incidence of severe infection.91 In a clinical trial conducted by Peng
MSCs treat ALF by differentiating into HLCs, regulating immune cells, and secreting therapeutic factors (Fig. 1). MSCs can differentiate into HLCs
No potential conflict of interest relevant to this article was reported.
Gut and Liver
Published online February 27, 2023
Copyright © Gut and Liver.
Yong-Hong Wang , En-Qiang Chen
Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
Correspondence to:En-Qiang Chen
ORCID https://orcid.org/0000-0002-8523-1689
E-mail chenenqiang1983@hotmail.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
Keywords: Acute liver failure, Mesenchymal stem cells, Hepatocyte-like cells, Immunomodulation
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. The first step in treating ALF is to remove the cause, such as alcohol withdrawal, anti-hepatitis virus, and discontinuation of liver-damaging drugs.1 The main treatments for ALF include conventional medical treatment, artificial liver support systems, and liver transplantation. Liver transplantation is the most effective treatment, but the lack of donor's livers and the high cost of transplantation limit its broad application.2,3 In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Meanwhile, stem cells are helpful in the treatment of many diseases, including liver failure, liver fibrosis, graft versus host disease, type 2 diabetes, etc.4-6
Stem cells are a kind of cells with self-replication, high proliferation, and multi-differentiation potential, which can exert therapeutic effects in various ways such as immunomodulation and tissue repair.7,8 Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their vast sources, low immunogenicity, and no ethical restrictions.9 Previous studies have shown that MSCs treat ALF by differentiating into hepatocyte-like cells (HLCs), regulating immune cells, and secreting therapeutic factors.10-12 Although MSCs are effective in treating ALF, the application of MSCs in ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSCs transplantation.
MSCs may differentiate into HLCs for tissue repair during the treatment of ALF. The induction method of stem cell-derived HLCs is phased induction by using cytokines.13-15 First, the MSCs were cultured in serum-free pretreatment medium (Iscove’s Modified Dulbecco’s Medium [IMDM]+20 ng/mL epidermal growth factor+10 ng/mL basic fibroblast growth factor [bFGF]) for 2 days. Then, the MSCs were cultured in differentiation inducing medium (IMDM+20 ng/mL hepatocyte growth factor [HGF]+10 ng/mL bFGF+nicotinamide 0.61 g/L) for 7 days. Finally, the MSCs were cultured in the maturation medium (IMDM+20 ng/mL oncostatin M+1 μmol/L dexamethasone+50 mg/mL insulin-transferrin-selenium) for 7 to 14 days. Although some scholars have adjusted the differentiation steps of HLCs, the key factors of the classical induction method are still retained.16-18 MSCs can be induced into HLCs
Whether HLCs have better efficacy in ALF than undifferentiated MSCs is uncertain. Wang
The overactivation of the immune system plays an essential role in initiating and accelerating ALF. MSCs can regulate the functions of various immune cells, so many studies have shown that MSCs treat ALF mainly through immune regulation. MSCs improve mitochondrial respiration and monocyte phagocytosis when monocytes are functionally exhausted in acute-on-chronic liver failure (ACLF) mice, thereby reducing liver injury and enhancing liver regeneration.28 However, the excessive activation of monocytes will aggravate ALF, and MSCs therapy can inhibit the activation of monocytes.29 Gazdic
Various substances derived from MSCs have therapeutic effects on ALF, including cytokines, conditioned medium (CM), and exosomes. Previous studies have shown MSC-derived cytokines such as IL-10, IL-4, HGF, PGE2, tumor necrosis factor-inducible gene 6 protein (TSG-6), and heme oxygenase 1 (HO-1) have therapeutic effects on ALF. MSCs can secrete IL-10 to alleviate liver failure, and inhibition of IL-10 secretion can reverse the therapeutic effect of MSCs. IL-10 may treat liver failure by improving mitochondrial damage of hepatocytes.39 Meanwhile, the anti-inflammatory effect of IL-10 may be mediated by STAT3 signaling pathway.40 MSCs attenuate hepatocyte necrosis by secreting HGF. When HGF in MSCs was knocked down, the therapeutic effect of MSCs on acetaminophen (APAP) induced ALF in mice was reduced.41 MSCs can promote the improvement of ALF by inducing hepatocyte proliferation through PGE2. PGE2 increases the expression of PGE4 and enhances the phosphorylation of cAMP response element-binding proteins, leading to the activation of Yes-associated protein (YAP) and the increase of YAP-related gene expression.42 Therefore, cytokines secreted by MSCs can treat ALF by reducing hepatocyte necrosis and promoting hepatocyte proliferation. Moreover, cytokines secreted by MSCs can also act on non-liver parenchymal cells to play a therapeutic role in ALF. Wang
Some studies found that MSC-CM and MSCs have similar therapeutic effects on ALF. MSC-CM is concentrated by ultrafiltration devices to increase the concentration of therapeutic factors. MSC-CM treatment profoundly inhibited hepatocyte death, enhanced liver regeneration, and improved survival in ALF rats.46 In another study, MSCs and MSC-CM exert the therapeutic effect of ALF by stimulating hepatocyte proliferation and inhibiting apoptosis, reducing macrophage infiltration, and transforming the CD4+T lymphocyte into an anti-inflammatory state.47 Parekkadan
In recent years, the application of MSCs-derived exosomes (MSC-Ex) in ALF has received extensive attention. Exosomes, a membranous extracellular vesicle with a diameter of 30 to 150 nm, carry a variety of proteins, nucleic acids, lipids, transcription factors, extracellular matrix proteins, enzymes and receptors, and play a role in treating diseases through these molecules.49 Bone marrow MSC-Ex can reduce hepatocyte oxidative stress
The effectiveness of MSCs in the treatment of ALF has been confirmed, but how to improve its efficacy is worth further study. Studies have reported that editing some target genes of MSCs can enhance the effectiveness of ALF, and the verified target genes include c-Met, C-C motif chemokine receptor 2 (CCR2), C-X-C motif chemokine receptor 4 (CXCR4), hepatocyte nuclear factor 4 alpha (HNF4α), IL-35, HGF, interleukin-1 receptor antagonist (IL-1Ra), forkhead box A2 (Foxa2), and VEGF165, etc. MSCs overexpressing some chemokines (c-Met, CCR2, and CXCR4) are more likely to reach the injured liver and improve the therapeutic effect of ALF.58-61 HNF4α overexpression enhances the therapeutic potential of MSCs in ALF mice by promoting the expression of IL-10 and inducing M2 polarization of macrophages.62 In Con A-induced acute hepatitis mice, MSCs overexpressing IL-35 can reduce the level of interferon gamma (IFN-γ) secreted by liver mononuclear cells through the janus kinase 1 (JAK1)-STAT1/STAT4 signaling pathway.63 Human umbilical cord MSCs overexpressing HGF attenuate liver injury and improve survival rate in ALF mice through anti-apoptosis and anti-oxidation mechanisms.64 In addition, IL-1Ra, an antagonist of IL-1, can promote liver regeneration and inhibit hepatocyte apoptosis after overexpression in MSCs.65 Chae
The pretreatment of MSCs with different stimuli before MSCs transplantation may improve the therapeutic efficacy of ALF. The pretreatment methods used in the experiment include edaravone, IL-1β, tumor necrosis factor-alpha (TNF-α), serum, etc. Edaravone elevating antioxidant levels in MSCs can significantly improve liver tissue repair capacity by increasing MSCs’ homing, promoting proliferation, reducing apoptosis, and increasing the secretion of HGF.68 Nie
Indeed, MSCs combined with other therapies may have better outcomes for ALF than MSCs therapy alone. The menstrual blood MSCs can alleviate liver injury by inhibiting Toll-like receptor 4 (TLR4) mediated PI3K/Akt/mTOR/IkappaB kinase (IKK) signaling pathway. Meanwhile, adenosine A2A receptor (A2AR) agonists can synergize with the menstrual blood MSCs.72 Sang
Some studies on the application and efficacy of MSCs in ALF animal models have been summarized in Table 1 to explore the optimal regimen of MSCs in treating ALF. MSCs have a wide range of tissue sources, including bone marrow, adipose tissue, umbilical cord, placenta, tonsils, etc.77-82 It is unclear whether MSCs from different tissue sources have similar therapeutic effects on ALF. Zare
Table 1 . The Application and Therapeutic Effect of MSCs in Animal Models of Acute Liver Failure.
MSCs type | Route | Dose (transplant frequency) | Transplant time | Inducer | Animal | Therapeutic effect and mechanism | Reference |
---|---|---|---|---|---|---|---|
hBMSCs | Portal vein | 3×106/kg (1 injection) | Injection immediately after using D-GalN | D-GalN | Pigs | Survival rate↑; inflammation↓; delta-like ligand 4 (DLL4)↑ | 81 |
AT-MSCs | Peripheral vein or splenic vein | 2×106/kg (2 injections) | Injections on day 3 and 8 after using CCL4 | CCL4 | Dogs | Liver enzymes↓; (IL-1, IL-6, IL-8, and IFN-γ)↓; (IL-4 , IL-10, HGF, and VEGFA)↑ | 82 |
BMSCs | Peripheral vein | 1×106/rat (1 injection) | Injections on 12 hr after using TAA | TAA | Rats | Survival rate↑; endotoxin↓; (IL-6 and TNF-α)↓ | 89 |
AT-MSCs | Peripheral vein | 2×105/rat (1 injection) | Injections on 2 hr after using APAP | APAP | Rats | Liver enzymes↓; (TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK)↓; (cyclin D1 and PCNA)↑ | 80 |
hUCMSCs | Peripheral vein | 2×106 or 4×106/rat (1 injection) | Injections on 1 hr after using LPS/D-GalN | LPS/D-GalN | Rats | Liver enzymes↓; (TNF-α, IFN-γ, IL-6, and IL-1β)↓; HGF↑; (Notch, IFN-γ/Stat1, and IL-6/Stat3 )↓ | 78 |
hUCMSCs | Peripheral vein | 5×105/mouse (1 injection) | Injections on 30 min before or after using APAP | APAP | Mice | Liver enzymes↓; (glutathione, superoxide dismutase)↑; (TNF-α and IL-6)↓; HGF↑ | 90 |
T-MSCs | Peripheral vein | 2×106/mouse (1 injection) | Injections on 30 min after using ConA or APAP | ConA or APAP | Mice | Liver enzymes↓; (INF-γ and TNF-α)↓; Galectin-1 is a key effector of T-MSCs | 79 |
hPMSCs | Portal vein or peripheral vein | 1×108/pig (1 injection) | Injections on 18 hr after using D-GalN | D-GalN | Pigs | Liver enzymes↓; (liver inflammation, hepatic denaturation and necrosis)↓; (liver regeneration)↑ | 77 |
MSCs, mesenchymal stem cells; hBMSCs, human bone MSCs; AT-MSCs, adipose tissue MSCs; BMSCs, bone MSCs; hUCMSCs, human umbilical cord MSCs; T-MSCs, tonsil-derived MSCs; hPMSCs, human placenta MSCs; D-GalN, D-galactosamine; CCL4, carbon tetrachloride; TAA, thioacetamide; APAP, acetaminophen; LPS, lipopolysaccharide; ConA, concanavalin A; IL, interleukin; IFN-γ, interferon gamma; HGF, hepatocyte growth factor; VEGFA, vascular endothelial growth factor A; TNF-α, tumor necrosis factor-alpha; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intercellular adhesion molecule-1; PCNA, proliferating cell nuclear antigen; Stat, signal transducer and activator of transcription..
The transplantation routes of MSCs include peripheral vein, portal vein, splenic vein, hepatic artery, intrahepatic injection, intrasplenic injection, etc. MSCs transplanted via tail vein and intrahepatic injection has similar efficacy in liver function and survival rate in ALF rats.85 Putra
The cell dose for MSCs transplantation increases proportionally to body weight in large animals (e.g., dogs and pigs), whereas it is fixed in small animals (e.g., mice and rats) (Table 1). ALF is progressing rapidly, so most studies use single MSCs transplantation, and the transplantation time is as early as possible (Table 1). MSCs transplantation (3×106 cells/kg) immediately after D-galactosamine injection can effectively treat ALF in pigs.81 Moreover, Jiang
Many studies have proved that MSCs can effectively treat ALF in animal models. Similarly, MSCs have therapeutic effects on patients with liver failure in clinical trials. In a randomized controlled trial, Peripheral infusion of allogeneic bone marrow MSCs is safe and effective in HBV-related ACLF patients, and significantly improves the 24-week survival rate by improving liver function and reducing the incidence of severe infection.91 In a clinical trial conducted by Peng
MSCs treat ALF by differentiating into HLCs, regulating immune cells, and secreting therapeutic factors (Fig. 1). MSCs can differentiate into HLCs
No potential conflict of interest relevant to this article was reported.
Table 1 The Application and Therapeutic Effect of MSCs in Animal Models of Acute Liver Failure
MSCs type | Route | Dose (transplant frequency) | Transplant time | Inducer | Animal | Therapeutic effect and mechanism | Reference |
---|---|---|---|---|---|---|---|
hBMSCs | Portal vein | 3×106/kg (1 injection) | Injection immediately after using D-GalN | D-GalN | Pigs | Survival rate↑; inflammation↓; delta-like ligand 4 (DLL4)↑ | 81 |
AT-MSCs | Peripheral vein or splenic vein | 2×106/kg (2 injections) | Injections on day 3 and 8 after using CCL4 | CCL4 | Dogs | Liver enzymes↓; (IL-1, IL-6, IL-8, and IFN-γ)↓; (IL-4 , IL-10, HGF, and VEGFA)↑ | 82 |
BMSCs | Peripheral vein | 1×106/rat (1 injection) | Injections on 12 hr after using TAA | TAA | Rats | Survival rate↑; endotoxin↓; (IL-6 and TNF-α)↓ | 89 |
AT-MSCs | Peripheral vein | 2×105/rat (1 injection) | Injections on 2 hr after using APAP | APAP | Rats | Liver enzymes↓; (TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK)↓; (cyclin D1 and PCNA)↑ | 80 |
hUCMSCs | Peripheral vein | 2×106 or 4×106/rat (1 injection) | Injections on 1 hr after using LPS/D-GalN | LPS/D-GalN | Rats | Liver enzymes↓; (TNF-α, IFN-γ, IL-6, and IL-1β)↓; HGF↑; (Notch, IFN-γ/Stat1, and IL-6/Stat3 )↓ | 78 |
hUCMSCs | Peripheral vein | 5×105/mouse (1 injection) | Injections on 30 min before or after using APAP | APAP | Mice | Liver enzymes↓; (glutathione, superoxide dismutase)↑; (TNF-α and IL-6)↓; HGF↑ | 90 |
T-MSCs | Peripheral vein | 2×106/mouse (1 injection) | Injections on 30 min after using ConA or APAP | ConA or APAP | Mice | Liver enzymes↓; (INF-γ and TNF-α)↓; Galectin-1 is a key effector of T-MSCs | 79 |
hPMSCs | Portal vein or peripheral vein | 1×108/pig (1 injection) | Injections on 18 hr after using D-GalN | D-GalN | Pigs | Liver enzymes↓; (liver inflammation, hepatic denaturation and necrosis)↓; (liver regeneration)↑ | 77 |
MSCs, mesenchymal stem cells; hBMSCs, human bone MSCs; AT-MSCs, adipose tissue MSCs; BMSCs, bone MSCs; hUCMSCs, human umbilical cord MSCs; T-MSCs, tonsil-derived MSCs; hPMSCs, human placenta MSCs; D-GalN, D-galactosamine; CCL4, carbon tetrachloride; TAA, thioacetamide; APAP, acetaminophen; LPS, lipopolysaccharide; ConA, concanavalin A; IL, interleukin; IFN-γ, interferon gamma; HGF, hepatocyte growth factor; VEGFA, vascular endothelial growth factor A; TNF-α, tumor necrosis factor-alpha; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intercellular adhesion molecule-1; PCNA, proliferating cell nuclear antigen; Stat, signal transducer and activator of transcription.