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    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

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Mesenchymal Stem Cell Therapy in Acute Liver Failure

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

Received: September 24, 2022; Revised: November 4, 2022; Accepted: November 18, 2022

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 2023;17(5):674-683. https://doi.org/10.5009/gnl220417

Published online February 27, 2023, Published date September 15, 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 in vitro, but whether MSCs can differentiate into HLCs in vivo is controversial. MSCs enter liver parenchyma and express human hepatocyte markers (albumin and α1-antitrypsin) after transplantation of green fluorescent protein-labeled human MSCs into liver-injured mice.19 However, some studies have found that transplanted MSCs failed to differentiate into HLCs by evaluating the distribution and hepatocyte markers of MSCs in vivo.20,21 The differentiation of MSCs into HLCs is identified from hepatocyte morphology, hepatocyte markers (e.g., albumin, alpha-fetoprotein, etc.), and hepatocyte function assays (e.g., glycogen storage, low-density lipoprotein uptake, indocyanine green uptake assays, and urea secretion, etc.).12,22,23

Whether HLCs have better efficacy in ALF than undifferentiated MSCs is uncertain. Wang et al.24 found that MSCs-derived HLCs expressed lower levels of HGF and had impaired immunosuppressive function compared to MSCs. Furthermore, undifferentiated MSCs are more effective than HLCs in treating ALF mice. Similarly, Zagoura et al.25 reported that HLCs could not colonize the liver and had no therapeutic effect on ALF. The possible reason for this phenomenon is that MSCs-derived HLCs lose the proliferation and colonization ability in the differentiation induction process. However, some studies have shown that undifferentiated MSCs and HLCs have similar effects on ALF. Human umbilical cord MSCs and HLCs transplanted from the tail vein were equally effective in entering the damaged liver tissue and improving the survival rate in ALF mice.26 Rat bone marrow MSCs and HLCs have similar effects in reducing transaminase levels and improving liver tissue damage in ALF rats.27 Notably, there is currently insufficient evidence that HLCs are more effective than undifferentiated MSCs in ALF.

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 et al.30 showed that indoleamine 2,3-dioxygenase derived from MSCs alleviated hepatotoxicity of natural killer T (NKT) cells by promoting the production of immunosuppressive interleukin (IL)-10 in T regulatory cells (Tregs). In addition, liver tissue-specific regulatory dendritic cells are induced by MSC-derived prostaglandin E2 (PGE2) and can increase the proportion of Tregs through transforming growth factor-β (TGF-β).31 Several studies have shown that MSCs can effectively treat ALF by inducing M2 polarization of macrophages.32-34 Wang et al.34 proved that MSC-derived PGE2 inhibits TGF-β activated kinase 1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation in hepatic macrophages, thereby reducing inflammatory cytokine production. Meanwhile, MSC-derived PGE2 can significantly increase the proportion of M2 macrophages in the liver through the signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) signaling pathways to reduce inflammation and liver injury.34 Meanwhile, MSCs mediate T cell apoptosis through Fas ligands, and the apoptotic T cells subsequently trigger macrophages to produce high levels of TGF-β, leading to upregulation of Tregs.35 MSCs attenuate ALF by inhibiting IL-17 production in hepatic NKT cells, whereas MSC treatment does not alter the ability of neutrophils and T lymphocytes to secrete IL-17.36 Zhao et al.37 observed that MSCs transplantation can improve liver injury in ALF rats by reducing the number and activity of neutrophils. Of note, the immune regulation of MSCs in ALF is systemic and not limited to the liver.37,38

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 et al.43 reported that MSC-derived IL-4 induced macrophage differentiation to the M2 anti-inflammatory phenotype to improve ALF in mice. In CCL4-induced ALF mice, TSG-6 secreted by MSCs promotes liver regeneration by inhibiting hepatic stellate cell activation. MSCs have essential anti-inflammatory and anti-apoptotic effects, which can improve ALF by increasing the expression of HO-1 and reducing the infiltration and function of neutrophils.44 In addition, MSC-derived HO-1 alleviates ALF by activating autophagy through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway.45

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 et al.48 found that MSC-CM containing therapeutic chemokines can alter leukocyte migration and inhibit inflammation in ALF rats. Human adipose-derived MSC-CM with high levels of HGF and vascular endothelial growth factor (VEGF) significantly improved survival in ALF rats.20 The therapeutic effect of MSC-CM may be the combination of soluble factors and exosomes because both are effective in treating ALF.

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 in vitro and promote liver regeneration in ALF rats.50 Meanwhile, MSC-Ex may alleviate ALF in mice by activating autophagy to inhibit hepatocyte apoptosis.51 Chen et al.52 found that human menstrual blood-derived MSC-Ex contains many cytokines including intercellular cell adhesion molecule-1, insulin-like growth factor binding protein-6, angiopoietin-2, Axl, osteoprotegerin, angiogenin, IL-6, and IL-8. MSC-Ex can migrate to the liver after transplantation, significantly improving liver function, increasing survival rate, and inhibiting hepatocyte apoptosis. Furthermore, MSC-Ex reduces the number of hepatic monocytes and the active apoptotic protein caspase-3 in injured livers.52 A single tail vein injection of human umbilical cord MSC-Ex can effectively improve survival rate, inhibit apoptosis of hepatocytes and improve liver function in APAP-induced ALF mice. The hepatoprotective effect of MSC-Ex is mainly to inhibit oxidative stress-induced apoptosis by up-regulating extracellular signal-regulated kinases 1/2 (ERK1/2); insulin-like growth factor-1 receptor (IGF-1R)/PI3K/Akt signaling pathway.53 In addition, previous studies have found that miRNA carried by MSC-Ex has a therapeutic effect on ALF.54,55 The miR-17 delivered by MSC-Ex plays an essential role in treating ALF by targeting thioredoxin interacting protein and inhibiting hepatic macrophage inflammasome activation.54 In CCL4 induced acute liver injury (ALI) mice, miR-455-3p derived from MSC-Ex can reduce macrophage infiltration and serum inflammatory factors, thus improving liver histology. The therapeutic mechanism of miR-455-3p may block the activation of the IL-6 signaling pathway in macrophages by targeting the phosphoinositide-3-kinase regulatory subunit 1 (PIK3r1) gene.55 Therefore, MSC-Ex, as an important mediator of stem cell therapy, also has a good therapeutic effect on ALF when used alone. The advantages of exosome therapy over conventional cell therapy are as follows. First, exosomes containing a variety of therapeutic factors are excellent drug delivery vehicles. Exosomes can reach the target organs through pulmonary capillaries and blood-brain barrier.56 Second, exosomes have a broader therapeutic dose range, whereas the risk of embolization increases with the dose of cell transplantation.57 Finally, the storage and use of exosomes are more convenient. Cell viability is a key factor affecting the efficacy of cell transplantation, which requires strict storage and use conditions. However, exosomes also have some disadvantages that limit their wide application. The main disadvantage is the lack of time-saving and low-cost exosome separation technology. Therefore, it is very difficult to obtain large quantities and high purity exosomes. In addition, stem cell transplantation has complete operation specifications, but exosome therapy is still in the initial stage, and there are no clinical trials using exosomes in liver diseases. The improvement of exosome isolation and purification technology can enable more exosome clinical trials to be carried out in the future. Meanwhile, more research is needed to standardize the process of exosome therapy, such as the source of exosomes, therapeutic dose, transplantation route and course of treatment.

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 et al.66 found that the overexpression of Foxa2 in MSCs enhances hepatocyte-like differentiation and alleviates ALI. The overexpression of VEGF165 enhances the pluripotency of MSCs and promotes the homing and colonization of MSCs in the liver.67

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 et al.69 reported that IL-1β (20 ng/mL) pretreatment could enhance the homing ability of MSCs by increasing the expression of CXCR4 and improving the efficacy of MSCs in treating ALF. Zhang et al.70 found that TNF-α (1 ng/mL) pretreated MSCs can secrete therapeutic exosomes to suppress NLRP3 activation in macrophages to improve ALF. Similarly, the serum of patients with liver failure contains a variety of pro-inflammatory and anti-inflammatory factors, and it is not clear whether MSCs function is affected by the serum. The role of MSCs is affected by the concentration of serum in ACLF patients. Ten percent (v/v) ACLF serum enhances the anti-inflammatory of MSCs by mediating the PI3K-Akt pathway, and 50% (v/v) ACLF serum promotes the transformation of MSCs to pro-inflammatory by affecting the cell cycle.71

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 et al.73 found that MSCs transplantation combined with IL-1Ra (2 mg/kg) can significantly improve the survival time of ALF swine, which may be related to the synergistic effect of MSCs and IL-1Ra in regulating inflammation and apoptosis. In ALF rat , Human umbilical cord blood MSCs transplantation combined granulocyte colony stimulating factor can reduce liver injury by inhibiting inflammation, oxidative stress, and hepatocyte apoptosis and promoting the proliferation and colonization of MSCs.74 In clinical trials of MSCs for liver failure patients, conventional medical treatment is fundamental, and MSCs are mainly used as adjuvant therapy.75 The artificial liver support system is an essential treatment for liver failure, among which plasma exchange is a commonly used method. In hepatitis B virus-related ACLF (HBV-ACLF) patients, MSCs combined with plasma exchange had the lowest mortality and adverse outcomes at 30, 60, and 90 days after treatment. However, the difference was not statistically significant.76

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 et al.83 reported that adipose-derived MSCs were more beneficial than bone marrow MSCs in terms of liver enzymes, histopathology, and survival rate in ALF mice. In addition, some scholars found that MSCs from different perinatal tissues from the same donor showed other therapeutic effects in ALF mice. The cord-placenta junction-derived MSCs and placenta-derived MSCs could improve the survival rate of ALF mice, but cord lining-derived MSCs had no difference from the controls.84 Therefore, the tissue source of MSCs may affect the efficacy of ALF. Notably, human-derived MSCs also have significant efficacy in animal models of ALF, reflecting the low immunogenicity of MSCs.

Table 1. The Application and Therapeutic Effect of MSCs in Animal Models of Acute Liver Failure

MSCs typeRouteDose (transplant frequency)Transplant timeInducerAnimalTherapeutic effect and mechanismReference
hBMSCsPortal vein3×106/kg (1 injection)Injection immediately after using D-GalND-GalNPigsSurvival rate↑; inflammation↓; delta-like ligand 4 (DLL4)↑81
AT-MSCsPeripheral vein or splenic vein2×106/kg (2 injections)Injections on day 3 and 8 after using CCL4CCL4DogsLiver enzymes↓; (IL-1, IL-6, IL-8, and IFN-γ)↓; (IL-4 , IL-10, HGF, and VEGFA)↑82
BMSCsPeripheral vein1×106/rat (1 injection)Injections on 12 hr after using TAATAARatsSurvival rate↑; endotoxin↓; (IL-6 and TNF-α)↓89
AT-MSCsPeripheral vein2×105/rat (1 injection)Injections on 2 hr after using APAPAPAPRatsLiver enzymes↓; (TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK)↓; (cyclin D1 and PCNA)↑80
hUCMSCsPeripheral vein2×106 or 4×106/rat (1 injection)Injections on 1 hr after using LPS/D-GalNLPS/D-GalNRatsLiver enzymes↓; (TNF-α, IFN-γ, IL-6, and IL-1β)↓; HGF↑; (Notch, IFN-γ/Stat1, and IL-6/Stat3 )↓78
hUCMSCsPeripheral vein5×105/mouse (1 injection)Injections on 30 min before or after using APAPAPAPMiceLiver enzymes↓; (glutathione, superoxide dismutase)↑; (TNF-α and IL-6)↓; HGF↑90
T-MSCsPeripheral vein2×106/mouse (1 injection)Injections on 30 min after using ConA or APAPConA or APAPMiceLiver enzymes↓; (INF-γ and TNF-α)↓; Galectin-1 is a key effector of T-MSCs79
hPMSCsPortal vein or peripheral vein1×108/pig (1 injection)Injections on 18 hr after using D-GalND-GalNPigsLiver 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 et al.86 showed that tail vein injection of MSCs is more effective than intraperitoneal injection in alleviating liver injury. Similarly, MSCs transplanted from the hepatic artery, portal vein, and tail vein had similar therapeutic effects on ALF, whereas MSCs injected intraperitoneally had no therapeutic effect on ALF.87 However, some studies have shown that portal vein administration is more effective than other transplantation routes. MSCs transplanted through portal veins can reduce liver inflammation and promote liver regeneration better than those administered through peripheral veins.77 Meanwhile, portal vein injection is superior to other MSCs transplantation routes, such as hepatic artery, peripheral vein and intrahepatic injection, in improving liver function, inhibiting hepatocyte apoptosis and prolonging survival time.88 The optimal route for MSCs transplantation in ALF remains unclear due to insufficient evidence at present.

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 et al.89 found that The transplantation of MSCs (1×106 cells) into each rat 12 hours after thioacetamide injection can effectively treat ALF. Some researchers tested three doses of MSCs (1×105, 5×105, 1×106 cells) in the ALF model and found that most mice died of ALF in the 1×105 cell group, while there was no difference in animal survival between the 5×105 cells group and the 1×106 cells group.90 Therefore, the MSCs transplantation should screen out the most appropriate cell dose, because excessive cell dose may lead to adverse reactions such as pulmonary embolism. The transplantation time of MSCs is almost always after an ALF inducing drug injection. A study compared the difference in the efficacy of stem cell transplantation 30 minutes before and 30 minutes after APAP injection and found that the early treatment group was higher than the delayed treatment group in improving the survival rate and reducing liver enzymes. However, the difference was not statistically significant.90

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 et al.,92 the albumin, total bilirubin and prothrombin time of patients were significantly improved after a single transplantation of autologous bone marrow MSCs via hepatic artery for 2 to 3 weeks. However, MSCs transplantation did not provide a survival benefit in liver failure patients at 192 weeks of follow-up. The course of MSCs therapy for liver failure is uncertain. Jia et al.93 found that extending the treatment from 4 to 8 weeks improves the efficacy of MSCs in treating end-stage liver disease. Notably, prolonging the treatment course may increase the cost of treatment and the incidence of adverse effects. Interestingly, some scholars have found that the age of liver failure patients is a factor affecting the efficacy of MSCs.94 Indeed, how to choose liver failure patients suitable for MSCs therapy needs to attract more attention.

MSCs treat ALF by differentiating into HLCs, regulating immune cells, and secreting therapeutic factors (Fig. 1). MSCs can differentiate into HLCs in vivo and in vitro, but only a small part of MSCs can differentiate into HLCs in vivo, and the induction of MSCs into HLCs in vitro does not improve the therapeutic effect of ALF. Therefore, HLCs do not play a dominant role in treating ALF, and it is unnecessary to treat ALF with HLCs. Notably, the immunomodulation mediated by MSCs is plastic, and MSCs can show pro-inflammatory or anti-inflammatory phenotypes under different stimuli. It is essential to know the immunomodulatory role of MSCs under various stimulation conditions. In addition, gene editing or pretreatment can increase the expression of therapeutic factors in MSCs and enhance the effect of MSCs in treating liver failure. MSCs are primarily used as monotherapy in animal models of ALF, while MSCs are combined with conventional therapies in clinical trials. Interestingly, the combination of MSCs with some therapeutic factors can improve the efficacy of ALF in animals. Therefore, the combination therapy of MSCs may have a good prospect. Indeed, the effectiveness of MSCs in treating ALF is affected by many factors, including tissue source, cell passage, transplantation route, transplantation time, transplantation frequency, cell dose, etc. Consequently, There are still many difficulties to be overcome in applying MSCs to the clinical treatment of ALF.

Figure 1.Mechanism and procedural improvement of mesenchymal stem cells (MSCs) in the treatment of acute liver failure.
NKT, natural killer T; A2AR, adenosine A2A receptor; IL-1Ra, interleukin-1 receptor antagonist; G-CSF, granulocyte colony stimulating factor.
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Article

Review Article

Gut and Liver 2023; 17(5): 674-683

Published online September 15, 2023 https://doi.org/10.5009/gnl220417

Copyright © Gut and Liver.

Mesenchymal Stem Cell Therapy in Acute Liver Failure

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

Received: September 24, 2022; Revised: November 4, 2022; Accepted: November 18, 2022

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.

Abstract

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

INTRODUCTION

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 DIFFERENTIATE INTO HLCs

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 in vitro, but whether MSCs can differentiate into HLCs in vivo is controversial. MSCs enter liver parenchyma and express human hepatocyte markers (albumin and α1-antitrypsin) after transplantation of green fluorescent protein-labeled human MSCs into liver-injured mice.19 However, some studies have found that transplanted MSCs failed to differentiate into HLCs by evaluating the distribution and hepatocyte markers of MSCs in vivo.20,21 The differentiation of MSCs into HLCs is identified from hepatocyte morphology, hepatocyte markers (e.g., albumin, alpha-fetoprotein, etc.), and hepatocyte function assays (e.g., glycogen storage, low-density lipoprotein uptake, indocyanine green uptake assays, and urea secretion, etc.).12,22,23

Whether HLCs have better efficacy in ALF than undifferentiated MSCs is uncertain. Wang et al.24 found that MSCs-derived HLCs expressed lower levels of HGF and had impaired immunosuppressive function compared to MSCs. Furthermore, undifferentiated MSCs are more effective than HLCs in treating ALF mice. Similarly, Zagoura et al.25 reported that HLCs could not colonize the liver and had no therapeutic effect on ALF. The possible reason for this phenomenon is that MSCs-derived HLCs lose the proliferation and colonization ability in the differentiation induction process. However, some studies have shown that undifferentiated MSCs and HLCs have similar effects on ALF. Human umbilical cord MSCs and HLCs transplanted from the tail vein were equally effective in entering the damaged liver tissue and improving the survival rate in ALF mice.26 Rat bone marrow MSCs and HLCs have similar effects in reducing transaminase levels and improving liver tissue damage in ALF rats.27 Notably, there is currently insufficient evidence that HLCs are more effective than undifferentiated MSCs in ALF.

MSCs MEDIATED IMMUNOMODULATION

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 et al.30 showed that indoleamine 2,3-dioxygenase derived from MSCs alleviated hepatotoxicity of natural killer T (NKT) cells by promoting the production of immunosuppressive interleukin (IL)-10 in T regulatory cells (Tregs). In addition, liver tissue-specific regulatory dendritic cells are induced by MSC-derived prostaglandin E2 (PGE2) and can increase the proportion of Tregs through transforming growth factor-β (TGF-β).31 Several studies have shown that MSCs can effectively treat ALF by inducing M2 polarization of macrophages.32-34 Wang et al.34 proved that MSC-derived PGE2 inhibits TGF-β activated kinase 1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation in hepatic macrophages, thereby reducing inflammatory cytokine production. Meanwhile, MSC-derived PGE2 can significantly increase the proportion of M2 macrophages in the liver through the signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) signaling pathways to reduce inflammation and liver injury.34 Meanwhile, MSCs mediate T cell apoptosis through Fas ligands, and the apoptotic T cells subsequently trigger macrophages to produce high levels of TGF-β, leading to upregulation of Tregs.35 MSCs attenuate ALF by inhibiting IL-17 production in hepatic NKT cells, whereas MSC treatment does not alter the ability of neutrophils and T lymphocytes to secrete IL-17.36 Zhao et al.37 observed that MSCs transplantation can improve liver injury in ALF rats by reducing the number and activity of neutrophils. Of note, the immune regulation of MSCs in ALF is systemic and not limited to the liver.37,38

MSCs SECRETE THERAPEUTIC MOLECULES

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 et al.43 reported that MSC-derived IL-4 induced macrophage differentiation to the M2 anti-inflammatory phenotype to improve ALF in mice. In CCL4-induced ALF mice, TSG-6 secreted by MSCs promotes liver regeneration by inhibiting hepatic stellate cell activation. MSCs have essential anti-inflammatory and anti-apoptotic effects, which can improve ALF by increasing the expression of HO-1 and reducing the infiltration and function of neutrophils.44 In addition, MSC-derived HO-1 alleviates ALF by activating autophagy through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway.45

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 et al.48 found that MSC-CM containing therapeutic chemokines can alter leukocyte migration and inhibit inflammation in ALF rats. Human adipose-derived MSC-CM with high levels of HGF and vascular endothelial growth factor (VEGF) significantly improved survival in ALF rats.20 The therapeutic effect of MSC-CM may be the combination of soluble factors and exosomes because both are effective in treating ALF.

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 in vitro and promote liver regeneration in ALF rats.50 Meanwhile, MSC-Ex may alleviate ALF in mice by activating autophagy to inhibit hepatocyte apoptosis.51 Chen et al.52 found that human menstrual blood-derived MSC-Ex contains many cytokines including intercellular cell adhesion molecule-1, insulin-like growth factor binding protein-6, angiopoietin-2, Axl, osteoprotegerin, angiogenin, IL-6, and IL-8. MSC-Ex can migrate to the liver after transplantation, significantly improving liver function, increasing survival rate, and inhibiting hepatocyte apoptosis. Furthermore, MSC-Ex reduces the number of hepatic monocytes and the active apoptotic protein caspase-3 in injured livers.52 A single tail vein injection of human umbilical cord MSC-Ex can effectively improve survival rate, inhibit apoptosis of hepatocytes and improve liver function in APAP-induced ALF mice. The hepatoprotective effect of MSC-Ex is mainly to inhibit oxidative stress-induced apoptosis by up-regulating extracellular signal-regulated kinases 1/2 (ERK1/2); insulin-like growth factor-1 receptor (IGF-1R)/PI3K/Akt signaling pathway.53 In addition, previous studies have found that miRNA carried by MSC-Ex has a therapeutic effect on ALF.54,55 The miR-17 delivered by MSC-Ex plays an essential role in treating ALF by targeting thioredoxin interacting protein and inhibiting hepatic macrophage inflammasome activation.54 In CCL4 induced acute liver injury (ALI) mice, miR-455-3p derived from MSC-Ex can reduce macrophage infiltration and serum inflammatory factors, thus improving liver histology. The therapeutic mechanism of miR-455-3p may block the activation of the IL-6 signaling pathway in macrophages by targeting the phosphoinositide-3-kinase regulatory subunit 1 (PIK3r1) gene.55 Therefore, MSC-Ex, as an important mediator of stem cell therapy, also has a good therapeutic effect on ALF when used alone. The advantages of exosome therapy over conventional cell therapy are as follows. First, exosomes containing a variety of therapeutic factors are excellent drug delivery vehicles. Exosomes can reach the target organs through pulmonary capillaries and blood-brain barrier.56 Second, exosomes have a broader therapeutic dose range, whereas the risk of embolization increases with the dose of cell transplantation.57 Finally, the storage and use of exosomes are more convenient. Cell viability is a key factor affecting the efficacy of cell transplantation, which requires strict storage and use conditions. However, exosomes also have some disadvantages that limit their wide application. The main disadvantage is the lack of time-saving and low-cost exosome separation technology. Therefore, it is very difficult to obtain large quantities and high purity exosomes. In addition, stem cell transplantation has complete operation specifications, but exosome therapy is still in the initial stage, and there are no clinical trials using exosomes in liver diseases. The improvement of exosome isolation and purification technology can enable more exosome clinical trials to be carried out in the future. Meanwhile, more research is needed to standardize the process of exosome therapy, such as the source of exosomes, therapeutic dose, transplantation route and course of treatment.

GENE EDITING OR PRETREATMENT TO MODIFY MSCs

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 et al.66 found that the overexpression of Foxa2 in MSCs enhances hepatocyte-like differentiation and alleviates ALI. The overexpression of VEGF165 enhances the pluripotency of MSCs and promotes the homing and colonization of MSCs in the liver.67

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 et al.69 reported that IL-1β (20 ng/mL) pretreatment could enhance the homing ability of MSCs by increasing the expression of CXCR4 and improving the efficacy of MSCs in treating ALF. Zhang et al.70 found that TNF-α (1 ng/mL) pretreated MSCs can secrete therapeutic exosomes to suppress NLRP3 activation in macrophages to improve ALF. Similarly, the serum of patients with liver failure contains a variety of pro-inflammatory and anti-inflammatory factors, and it is not clear whether MSCs function is affected by the serum. The role of MSCs is affected by the concentration of serum in ACLF patients. Ten percent (v/v) ACLF serum enhances the anti-inflammatory of MSCs by mediating the PI3K-Akt pathway, and 50% (v/v) ACLF serum promotes the transformation of MSCs to pro-inflammatory by affecting the cell cycle.71

COMBINATION THERAPY OF MSCs

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 et al.73 found that MSCs transplantation combined with IL-1Ra (2 mg/kg) can significantly improve the survival time of ALF swine, which may be related to the synergistic effect of MSCs and IL-1Ra in regulating inflammation and apoptosis. In ALF rat , Human umbilical cord blood MSCs transplantation combined granulocyte colony stimulating factor can reduce liver injury by inhibiting inflammation, oxidative stress, and hepatocyte apoptosis and promoting the proliferation and colonization of MSCs.74 In clinical trials of MSCs for liver failure patients, conventional medical treatment is fundamental, and MSCs are mainly used as adjuvant therapy.75 The artificial liver support system is an essential treatment for liver failure, among which plasma exchange is a commonly used method. In hepatitis B virus-related ACLF (HBV-ACLF) patients, MSCs combined with plasma exchange had the lowest mortality and adverse outcomes at 30, 60, and 90 days after treatment. However, the difference was not statistically significant.76

EXPLORING THE OPTIMAL REGIMEN OF MSCs THERAPY FOR ALF

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 et al.83 reported that adipose-derived MSCs were more beneficial than bone marrow MSCs in terms of liver enzymes, histopathology, and survival rate in ALF mice. In addition, some scholars found that MSCs from different perinatal tissues from the same donor showed other therapeutic effects in ALF mice. The cord-placenta junction-derived MSCs and placenta-derived MSCs could improve the survival rate of ALF mice, but cord lining-derived MSCs had no difference from the controls.84 Therefore, the tissue source of MSCs may affect the efficacy of ALF. Notably, human-derived MSCs also have significant efficacy in animal models of ALF, reflecting the low immunogenicity of MSCs.

Table 1 . The Application and Therapeutic Effect of MSCs in Animal Models of Acute Liver Failure.

MSCs typeRouteDose (transplant frequency)Transplant timeInducerAnimalTherapeutic effect and mechanismReference
hBMSCsPortal vein3×106/kg (1 injection)Injection immediately after using D-GalND-GalNPigsSurvival rate↑; inflammation↓; delta-like ligand 4 (DLL4)↑81
AT-MSCsPeripheral vein or splenic vein2×106/kg (2 injections)Injections on day 3 and 8 after using CCL4CCL4DogsLiver enzymes↓; (IL-1, IL-6, IL-8, and IFN-γ)↓; (IL-4 , IL-10, HGF, and VEGFA)↑82
BMSCsPeripheral vein1×106/rat (1 injection)Injections on 12 hr after using TAATAARatsSurvival rate↑; endotoxin↓; (IL-6 and TNF-α)↓89
AT-MSCsPeripheral vein2×105/rat (1 injection)Injections on 2 hr after using APAPAPAPRatsLiver enzymes↓; (TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK)↓; (cyclin D1 and PCNA)↑80
hUCMSCsPeripheral vein2×106 or 4×106/rat (1 injection)Injections on 1 hr after using LPS/D-GalNLPS/D-GalNRatsLiver enzymes↓; (TNF-α, IFN-γ, IL-6, and IL-1β)↓; HGF↑; (Notch, IFN-γ/Stat1, and IL-6/Stat3 )↓78
hUCMSCsPeripheral vein5×105/mouse (1 injection)Injections on 30 min before or after using APAPAPAPMiceLiver enzymes↓; (glutathione, superoxide dismutase)↑; (TNF-α and IL-6)↓; HGF↑90
T-MSCsPeripheral vein2×106/mouse (1 injection)Injections on 30 min after using ConA or APAPConA or APAPMiceLiver enzymes↓; (INF-γ and TNF-α)↓; Galectin-1 is a key effector of T-MSCs79
hPMSCsPortal vein or peripheral vein1×108/pig (1 injection)Injections on 18 hr after using D-GalND-GalNPigsLiver 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 et al.86 showed that tail vein injection of MSCs is more effective than intraperitoneal injection in alleviating liver injury. Similarly, MSCs transplanted from the hepatic artery, portal vein, and tail vein had similar therapeutic effects on ALF, whereas MSCs injected intraperitoneally had no therapeutic effect on ALF.87 However, some studies have shown that portal vein administration is more effective than other transplantation routes. MSCs transplanted through portal veins can reduce liver inflammation and promote liver regeneration better than those administered through peripheral veins.77 Meanwhile, portal vein injection is superior to other MSCs transplantation routes, such as hepatic artery, peripheral vein and intrahepatic injection, in improving liver function, inhibiting hepatocyte apoptosis and prolonging survival time.88 The optimal route for MSCs transplantation in ALF remains unclear due to insufficient evidence at present.

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 et al.89 found that The transplantation of MSCs (1×106 cells) into each rat 12 hours after thioacetamide injection can effectively treat ALF. Some researchers tested three doses of MSCs (1×105, 5×105, 1×106 cells) in the ALF model and found that most mice died of ALF in the 1×105 cell group, while there was no difference in animal survival between the 5×105 cells group and the 1×106 cells group.90 Therefore, the MSCs transplantation should screen out the most appropriate cell dose, because excessive cell dose may lead to adverse reactions such as pulmonary embolism. The transplantation time of MSCs is almost always after an ALF inducing drug injection. A study compared the difference in the efficacy of stem cell transplantation 30 minutes before and 30 minutes after APAP injection and found that the early treatment group was higher than the delayed treatment group in improving the survival rate and reducing liver enzymes. However, the difference was not statistically significant.90

CLINICAL TRIALS OF MSCs IN THE TREATMENT OF LIVER FAILURE

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 et al.,92 the albumin, total bilirubin and prothrombin time of patients were significantly improved after a single transplantation of autologous bone marrow MSCs via hepatic artery for 2 to 3 weeks. However, MSCs transplantation did not provide a survival benefit in liver failure patients at 192 weeks of follow-up. The course of MSCs therapy for liver failure is uncertain. Jia et al.93 found that extending the treatment from 4 to 8 weeks improves the efficacy of MSCs in treating end-stage liver disease. Notably, prolonging the treatment course may increase the cost of treatment and the incidence of adverse effects. Interestingly, some scholars have found that the age of liver failure patients is a factor affecting the efficacy of MSCs.94 Indeed, how to choose liver failure patients suitable for MSCs therapy needs to attract more attention.

CONCLUSION

MSCs treat ALF by differentiating into HLCs, regulating immune cells, and secreting therapeutic factors (Fig. 1). MSCs can differentiate into HLCs in vivo and in vitro, but only a small part of MSCs can differentiate into HLCs in vivo, and the induction of MSCs into HLCs in vitro does not improve the therapeutic effect of ALF. Therefore, HLCs do not play a dominant role in treating ALF, and it is unnecessary to treat ALF with HLCs. Notably, the immunomodulation mediated by MSCs is plastic, and MSCs can show pro-inflammatory or anti-inflammatory phenotypes under different stimuli. It is essential to know the immunomodulatory role of MSCs under various stimulation conditions. In addition, gene editing or pretreatment can increase the expression of therapeutic factors in MSCs and enhance the effect of MSCs in treating liver failure. MSCs are primarily used as monotherapy in animal models of ALF, while MSCs are combined with conventional therapies in clinical trials. Interestingly, the combination of MSCs with some therapeutic factors can improve the efficacy of ALF in animals. Therefore, the combination therapy of MSCs may have a good prospect. Indeed, the effectiveness of MSCs in treating ALF is affected by many factors, including tissue source, cell passage, transplantation route, transplantation time, transplantation frequency, cell dose, etc. Consequently, There are still many difficulties to be overcome in applying MSCs to the clinical treatment of ALF.

Figure 1. Mechanism and procedural improvement of mesenchymal stem cells (MSCs) in the treatment of acute liver failure.
NKT, natural killer T; A2AR, adenosine A2A receptor; IL-1Ra, interleukin-1 receptor antagonist; G-CSF, granulocyte colony stimulating factor.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig 1.

Figure 1.Mechanism and procedural improvement of mesenchymal stem cells (MSCs) in the treatment of acute liver failure.
NKT, natural killer T; A2AR, adenosine A2A receptor; IL-1Ra, interleukin-1 receptor antagonist; G-CSF, granulocyte colony stimulating factor.
Gut and Liver 2023; 17: 674-683https://doi.org/10.5009/gnl220417

Table 1 The Application and Therapeutic Effect of MSCs in Animal Models of Acute Liver Failure

MSCs typeRouteDose (transplant frequency)Transplant timeInducerAnimalTherapeutic effect and mechanismReference
hBMSCsPortal vein3×106/kg (1 injection)Injection immediately after using D-GalND-GalNPigsSurvival rate↑; inflammation↓; delta-like ligand 4 (DLL4)↑81
AT-MSCsPeripheral vein or splenic vein2×106/kg (2 injections)Injections on day 3 and 8 after using CCL4CCL4DogsLiver enzymes↓; (IL-1, IL-6, IL-8, and IFN-γ)↓; (IL-4 , IL-10, HGF, and VEGFA)↑82
BMSCsPeripheral vein1×106/rat (1 injection)Injections on 12 hr after using TAATAARatsSurvival rate↑; endotoxin↓; (IL-6 and TNF-α)↓89
AT-MSCsPeripheral vein2×105/rat (1 injection)Injections on 2 hr after using APAPAPAPRatsLiver enzymes↓; (TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK)↓; (cyclin D1 and PCNA)↑80
hUCMSCsPeripheral vein2×106 or 4×106/rat (1 injection)Injections on 1 hr after using LPS/D-GalNLPS/D-GalNRatsLiver enzymes↓; (TNF-α, IFN-γ, IL-6, and IL-1β)↓; HGF↑; (Notch, IFN-γ/Stat1, and IL-6/Stat3 )↓78
hUCMSCsPeripheral vein5×105/mouse (1 injection)Injections on 30 min before or after using APAPAPAPMiceLiver enzymes↓; (glutathione, superoxide dismutase)↑; (TNF-α and IL-6)↓; HGF↑90
T-MSCsPeripheral vein2×106/mouse (1 injection)Injections on 30 min after using ConA or APAPConA or APAPMiceLiver enzymes↓; (INF-γ and TNF-α)↓; Galectin-1 is a key effector of T-MSCs79
hPMSCsPortal vein or peripheral vein1×108/pig (1 injection)Injections on 18 hr after using D-GalND-GalNPigsLiver 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.


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Gut and Liver

Vol.18 No.3
May, 2024

pISSN 1976-2283
eISSN 2005-1212

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