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Abstract

Liver transplantation has been deemed the best choice for end-stage liver disease patients but immune rejection after surgery is still a serious problem. Patients have to take immunosuppressive drugs for a long time after liver transplantation, and this often leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to researchers because of their powerful immunomodulatory effects. In the past, a large number of in vitro and in vivo studies have demonstrated the great potential of MSCs for participation in posttransplant immunomodulation. In addition, MSCs also have properties that may potentially benefit patients undergoing liver transplantation. This article aims to provide an overview of the current understanding of the immunomodulation achieved by the application of MSCs in liver transplantation, to discuss the problems that may be encountered when using MSCs in clinical practice, and to describe some of the underlying capabilities of MSCs in liver transplantation. Cell–cell contact, soluble molecules, and exosomes have been suggested to be critical approaches to MSCs’ immunoregulation in vitro; however, the exact mechanism, especially in vivo, is still unclear. In recent years, the clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to the clinical application of MSCs are decreasing, but large sample clinical trials involving MSCs are still needed to further study their clinical effects.

Keywords

mesenchymal stromal cells liver transplantation immunosuppression tolerance clinical trial

Introduction

Liver transplantation has been deemed the best therapy for end-stage liver diseases, but recipients usually have to live with life-long immunosuppression¹ (Figure 1). Although the standard pharmacological immunosuppressive treatment commonly used in clinical practice can achieve the favorable results of long grafts and patients survival rates, the side effects (Figure 1) caused by the treatment are significant². In addition to the drug toxicities, the risks of malignancies and opportunistic infections have been reported to be increasing significantly³. Immunomodulatory cell therapy, as a complementary plan to standard pharmacological immunosuppression, appears to be a solution to this problem. In transplantation cases, the ultimate goal of immunomodulatory cell therapy is to prolong solid-organ allograft survival with reduced, or even no, usage of systemic pharmacological immunosuppression⁴.

Figure 1.

Common classes of immunosuppressive drugs in liver transplantation and the main side effects of immunosuppressive drugs.

Mesenchymal stem cells (MSCs), a subpopulation of multipotent and non-hematopoietic cells initially isolated from bone marrow and reported by Friedenstein et al. in 1970^5,6, are also called mesenchymal stromal cells and have been the focus of transplant scientists due to their great potential capacities for tissue repair and immunomodulation. Although no reports of large-scale clinical practices involving MSCs for liver transplantation have been found, and MSCs investigations remain mostly at the preclinical stage, the powerful immunomodulatory properties shown in recent reports make MSCs a promising candidate therapy in clinical liver transplantation. In addition, the effects of MSCs can be improved through gene modification and pretreatment, and the potential properties of MSCs show great promise in liver transplantation.

Research Status of MSCs

Cell therapy for immune rejection after organ transplantation is characterized mainly by its powerful immunomodulatory function. Although the immunomodulatory property seems to be a shared feature of all stromal cells including MSCs and fibroblasts, the characteristics of MSCs (such as easy cultivation, expansion, and storage in vitro) make them more appropriate for organ transplantation^7
–9. Based on these characteristics, MSCs have been studied for immunosuppression after transplantation of various organs, including the liver, kidney, skin, etc.

MSCs can be isolated from diverse sources, such as umbilical cord blood, peripheral blood, and adipose tissue, and all MSCs share many characteristics, including cell phenotype and immunomodulatory properties^10

–15. MSCs can also be isolated from some other species such as mice, rats, and rabbits, and great differences exist among them in many aspects, such as the mechanisms of their immunomodulatory properties¹⁶. Moreover, MSCs isolated from different human tissues do not have the identical properties. For example, all MSCs secrete different cytokines, which may affect their immunosuppressive effects¹⁷. A unique and definitive marker has not yet been found for MSCs isolated from various sources; however, it is known that they lack the expression of major histocompatibility complex class II and costimulatory molecules (including CD80, CD86, and CD40), and this characteristic appears to explain the low immunogenicity of MSCs¹⁸. Due to this low immunogenicity, in in vitro mixed lymphocyte reaction (MLR) experiments, even MSCs from third-party sources barely caused a lymphocyte response^19,20. Thus, some authors believe that MSCs from the recipient, donor, and even third-party sources could be feasible in organ transplantation, although this is not yet widely accepted due to the lack of research evidence in the human body and the effects not being entirely satisfactory²¹.

In general, as the first tissue from which MSCs were isolated, bone marrow (BM) is currently the main source of MSCs for investigation. In clinical studies of organ transplantation, the most widely accepted practice is to choose MSCs isolated from the BM of the donor or the recipient; however, researchers are keen on seeking alternative sources of MSCs such as urine, placenta, and adipose tissue, due to the limited quantities and difficulty in isolating BM-MSCs. MSCs from other sources also have their own immunoregulatory characteristics. Although it is still unclear, and there is a lack of clinical evidence about which type of MSCs is most suitable for immunoregulation after liver transplantation, recent studies have revealed differences in MSCs from diverse sources. For instance, Rho et al. demonstrated that adipose-MSCs (A-MSCs) and BM-MSCs expressed high levels of IL-10 and TGF-β, and dermal skin-MSCs expressed high levels of IFN-γ²². The same dose of melatonin treatment for A-MSCs and BM-MSCs had different degrees of influence on viability²³. Moreover, the function of MSCs from the same source may also be different. A study showed that aged BM-MSCs secrete more IL-6 and exerted stronger immunomodulatory effects than young BM-MSCs²⁴. Considering that the differences among these MSCs may have different outcomes in patients undergoing liver transplantation, the above studies indicate that doctors could choose personalized medicine regimens based on MSCs according to the conditions of their patients in the future, though much research is still needed to achieve this goal.

MSC In Vitro Studies

The results of in vitro experiments have indicated the powerful immunomodulatory capacity of MSCs, which could influence almost all cells involved in the immune reaction (Table 1). For B cells, MSCs can inhibit B cell differentiation and proliferation, most likely by directly contact between MSCs and T cells, and by arresting B cells in the G0/G1 phase of the cell cycle^25

–28. For natural killer (NK) cells, MSCs can inhibit their activation and proliferation in a dose-dependent manner^29,37. Secreted factors, including interferon-γ (IFN-γ), prostaglandin E2 (PGE2), transforming growth factor β (TGF-β), and indoleamine 2,3-dioxygenase (IDO), as well as cell-to-cell contact might be involved in this process^29,30. Regarding dendritic cells (DCs), MSCs could influence their differentiation, maturation, and function by direct interaction and soluble mediators, such as prostaglandin E2 (PGE2) and IL-6³¹. In detail, MSCs can interfere with the differentiation of DCs, maintain DCs in the immature stage and suppress pro-inflammatory cytokine release by DCs^31,32. And, dependent on maturation inducers, coculture of MSCs with DCs could also upregulate the expression of PD-L1 in DCs, and results indicate that MSCs could induce tolerogenic DCs by manipulating the molecular phenotype of DCs³³. Additionally, researchers have become gradually aware of the importance of exosomes from MSCs in immunoregulation, and have performed large scale studies³⁸. The role of MSC-derived exosomes in liver transplantation will be discussed in the following sections.

Table 1.

The Effects of MSCs on Immune Cells.

Immune cells	Effects	References
B-cells	MSCs could inhibit B-cell differentiation and proliferation, and arrest B cells in the G0/G1 phase of the cell cycle.	^25 –28
NK-cells	MSCs could inhibit NK cells activation and proliferation. in a dose-dependent manner	^29,30
DCs	MSCs could maintain DCs in an immature stage, suppress pro-inflammatory cytokine release and upregulate the expression of PD-L1in DCs.	^31 –33
T-cells	MSCs could suppress T cells’ proliferation activation and differentiation through cell-cell contact that is mediated by PD-L1, and soluble molecules.	^34,35
Kupffer cells	MSCs could reprogram Kupffer cells	³⁶

For investigations in organ transplantation, suppressing the function of T cells plays the most important role among the immunomodulatory properties of MSCs³⁹. Previous studies have confirmed that MSCs can inhibit T cell activation and proliferation, promote T cell apoptosis in vitro, and regulate the T cell subset ratio by increasing Treg and Th2, as well as decreasing Th1 and Th17 cells^40
–42. Regarding the mechanism of T cell suppression, some authors believe that the inhibition of DC maturation and phenotype is closely involved^43,44. However, if only CD4+ T cells (with phytohemagglutinin stimulation) and MSCs are present, the immunosuppressive effect of MSCs on T-cell proliferation still works⁴⁵. Cell–cell contact was deemed to be important for this immunosuppressive property of MSCs. Specifically, cell–cell contact was found to be crucial for regulatory T cell induction, and direct contact through the programmed death (PD) 1 inhibitory pathway was considered to be involved in the inhibitory effects on T cell activation and proliferation³⁴. As well as direct contact, soluble molecules are also thought to mediate T cell suppression because MSCs could still suppress T cell proliferation even without cell–cell contact³⁵. Molecules possibly involved in human MSCs, as they are known, include transforming growth factor (TGF), hepatocyte growth factor (HGF), IDO, PGE2, insulin-like growth factor binding proteins, heme oxygenase-1 (HO), human histocompatibility antigen-G5 (HLA-G5), chemokine (C-C motif) ligand 2 (CCL2), IL-10, galectin-1, and galectin-3^{35,46

–55}. All these molecules were found to be involved in T cell suppression. There have been some recent studies on the mechanism of interaction between cytokines derived from MSCs and T-cells. For instance, studies have shown that cytokines derived from MSCs could participate in the inhibition of T cells by regulating expression of the FoxP3 gene ^34,38. However, the mechanism governing cytokine interactions between MSCs and FoxP3 is not completely clear, and these studies explained only part of the mechanisms linking cytokines and T-cells. Thus, the mechanism of the effects of MSC-derived cytokines on T cells is still the focus of research.

Macrophages have also been found to be involved in the immunosuppressive capacity of MSCs, and recently authors have begun to pay attention to MSC regulation of macrophages to achieve the goal of treating some specific diseases⁵⁶. Németh et al. observed inhibition of the systemic inflammatory response and prolonged survival of rats after infusing MSCs into rats with sepsis⁵⁷. Moreover, the immunoregulatory property of MSCs still existed after T cells, B cells, or NK cells were depleted, but the effect was eliminated when macrophages were depleted⁵⁶. This result proved the critical role played by macrophages in MSC-mediated immunoregulation. This observation might be quite important in the application of MSCs in liver transplantation and we shall further discuss this issue below.

MSC In Vivo Studies

Concerning in vivo studies, MSCs have been found to play a role in various diseases, such as relieving illness in patients with systemic lupus erythematosus (SLE), ameliorating diabetes in a murine model, reducing inflammatory MRI parameters in multiple sclerosis (MS) patients, and preventing lethal graft-versus-host disease (GVHD) in clinical patients^58

-61. Although much knowledge has been accumulated in term of the immunoregulatory properties of MSCs, the exact mechanism remains undefined and unclear⁶². Moreover, because of the different conditions between in vivo and in vitro studies, research data in vitro could not comprehensively explain results in vivo. For example, due to lack of direct cell–cell interaction, the cell–cell contact that was deemed critical in MSC immunosuppression in vitro is no longer believed to be critical. Therefore, the mechanism of the immunoregulatory property of MSCs in vivo needs to be investigated further.

In transplantation, their immunosuppressive property and low immunogenicity could allow MSCs to induce immunosuppression in vivo without rejection, which makes MSCs suitable for organ transplantation. In animal experiments (Table 2), many successful cases of MSC application in organ transplantation, including heart, skin, kidney, and liver^83
–85, have been reported, supporting the use of MSCs in clinical patients. In clinical trials, since BM-MSCs were first used as immunomodulators in a patient with GVHD, several studies have supported the safety and feasibility of BM-MSC use in autologous and allogeneic organ transplantation through a large number of experiments^86
–88. In the past, researchers were generally concerned about the long-term complications of MSCs, such as tumors and infections. To date, all clinical studies on MSCs and liver transplantation that have been published have confirmed the safety and feasibility of use of MSCs in the human body^89

–92. Additionally, dozens of studies in other tissues have also proven the safety of MSC transplantation⁹³. However, because the sample size of the previously described liver transplantation study was small and the follow-up period was short, the role of MSCs in cancer progression remains controversial, and more samples and longer-term clinical trials are still needed to support the application of MSCs in liver transplantation patients, especially those with hepatocellular carcinoma.

Table 2.

Liver Transplantation Trials Based on MSCs in Animal Models.

Source of cells	Model	Injection dose	Mechanism	Conclusion	References
BM-MSCs	Guinea pig model	1 × 10⁷	MSCs interfere with recipient humoral immunity.	MSCs alleviated hyperacute immune rejection in xenogeneic liver transplantation.	⁶³
A-MSCs	Rat model	2 × 10⁶	A- MSCs inhibited T-cell proliferation.	A-MSCs relieved acute rejection following orthotopic and relieved hepatic ischemia reperfusion injury liver transplantation in rats.	⁶⁴
BM-MSCs	Rat model	5 × 10⁶	MSCs pretreated with IFN-γ expressed higher level of PDL-1, MHC-I, MHC-II, and CD54 than MSCs without pretreatment.	IFN-γ enhances the immunosuppressive function of MSCs to protect liver allografts.	⁶⁵
A-MSCs	Dog model	–	The stem cells transplanted differentiated into mature hepatocyte-like cells and secreted albumin in the hepatic tissue.	Autologous MSCs infusion through the portal vein prolonged the survival of the recipient dogs and promoted the recovery of damaged liver function.	⁶⁶
HGF overexpressing MSCs	Rat model	2-5 × 10⁶	HGF-overexpressing MSCs significantly alleviated acute rejection after liver transplantation and countered liver fibrosis through synergistic action with hepatic stellate cells.	HGF-overexpressing MSCs improved the survival rate of transplantation compared with BM-MSCs.	^67 –69
BM-MSCs	Rat model	1-5 × 10⁶	MSCs regulated immune responses by increasing the Treg ratio and prompting Kupffer cell M2 polarization.	MSCs administered after liver transplantation prevented GVHD, and early injection after transplantation is recommended.	^36,70,71,72
TGF-β overexpressing MSCs	Rat model	5× 10⁶	TGF-β overexpressing MSCs increased CD4 + Foxp3 + Helios- induced Tregs and decreased Th17cells.	TGF-β overexpressing MSCs could significantly alleviate immune rejection.	⁷³
HO-1 overexpressing MSCs	Rat model	5 × 10⁶-1×10⁷	HO-MSCs had stronger immune regulation than normal MSCs and could promote liver function recovery by regulating autophagy.	Heme oxygenase-1(HO-1) enhanced and prolonged the effect of MSCs on GVHD of normal and reduced-size liver transplantation and promoted liver function recovery.	^74 –76
BM-MSCs	Rat model	0.5-3× 10⁶/kg	BM-MSCs reduced ischemia-reperfusion injury, regulate T cell ratio and prevent Kupffer cell apoptosis.	BM-MSCs effectively improved the success rate of liver transplantation from donors after cardiac death.	^77,78
BM-MSCs	Rat model	2.4×10⁶	MSCs upregulates the expression of transcription factors AP-1, NF-κB, p-c-Jun and CyD1 in grafts.	MSCs prolonged survival in small-for-size liver grafts.	⁷⁹
IL-10 overexpressing MSCs	Rat model	2.5×10⁵	IL-10 increases the immunoregulatory capacity of MSCs.	Compared with normal MSCs, IL-10 overexpressing MSCs had stronger effects on GVHD in liver transplantation.	⁸⁰
A-MSCs	Rat model	–	MiR-27b inhabited the expression of CXCL12 in A-MSCs and thereby inducing T cell proliferation.	MiR-27b participated in immune suppression after liver transplantation mediated by MSCs.	⁸¹
CXCR4 over expressing MSCs	Rat model	1×10⁷	CXCR4 overexpression enhanced the mobilization and engraftment of MSCs in liver transplantation.	CXCR4 over ex-pressing MSCs promoted early liver regeneration of small-for-size liver transplantation.	⁸²

Current clinical studies focus mainly on the safety and feasibility of MSCs, but some in vivo animal trials that improved the immunomodulatory capacity and homing ability of MSCs through phenotypic modification or pretreatment have been carried out and have acquired good results. For example, researchers have enhanced the efficiency of MSCs by expressing the TNF-αR-Fc and HO-1 genes in porcine islet xenotransplantation mouse models⁹⁴. However, whether this treatment can benefit liver transplant recipients needs further study.

Current Status of Clinical Liver Transplantation

Since the first case of human orthotopic liver transplantation was described in 1963, liver transplantation has undergone 50 years of development, with the 1-year survival rate increasing from 25% to more than 85%^34,95. However, the problem of immune rejection after surgery still exists, with more than 30% of liver transplant recipients still suffering varying degrees of rejection (Figure 2)⁹⁶. Nevertheless, the incidence and severity of rejection after liver transplantation remains much lower than that in other solid organs, which makes the liver an “immunologically privileged organ”. From the perspective of physiology, given its exposure to numerous foreign materials from the gut, the liver is necessarily a tolerogenic organ, and the tolerance of the liver plays a key role in preventing potentially devastating inflammatory responses against both food and normal enteric bacteria⁹⁷. Although the phenomenon of “liver tolerance” has been described for decades, the exact mechanism is yet not thoroughly understood. All the theories involving T cell anergy induction and regulatory DC induction cannot completely explain this phenomenon⁹⁸. However, it is sure that the liver microenvironment, especially the environment around the hepatic sinusoid, plays a critical role in maintaining liver tolerance. Xia et al. described changes in the microenvironment status that could affect the state of liver tolerance⁹⁹. On the other hand, changing and influencing the local immune microenvironment is considered to be an important MSC immunomodulatory property, which makes MSCs excellent candidate cells for promoting and maintaining liver graft tolerance.

Figure 2.

Mechanism of immune rejection after liver transplantation. Donor antigens are recognized by antigen-presenting cells (APCs) and transferred to T cells. After activation, T cells differentiate into various effector T cells to secrete inflammatory factors or directly participate in immune rejection. B cells are activated with or without the help of Th2 cells after recognition of the donor antigens, secreting antibodies and cytokines that act on donor cells.

Although some immunocytes including NK cells, DCs, and T cells have already been deemed to be involved in the liver tolerance mechanism, some other factors should be considered for the explanation of liver tolerance, considering that those cells exist all over the body¹⁰⁰. Kupffer cells (KCs)—the macrophages located in the hepatic sinusoid—account for 75%–80% of the macrophages in the whole body, and are known to be one of the key factors that make the microenvironment of the hepatic sinusoid different from that in other organs¹⁰¹. Several decades ago, Callery et al. reported that blocking KCs could inhibit the induction of liver tolerance, thus proving the critical role of KCs in liver tolerance¹⁰². However, the role of KCs in immunity is ambiguous because they could both prevent liver injury and aggravate liver injury under different conditions¹⁰³. Our previous results and those of other studies demonstrated that switching KCs from pro-inflammatory to anti-inflammatory status could promote hepatic immune tolerance^36,104. Considering the influence of MSCs on macrophages, and the similarities between KCs and macrophages, MSCs could possibly reprogram the immune status of KCs. In fact, we already have evidence indicating that the MSC-dependent reprogramming of KCs is crucial for liver transplant tolerance³⁶. Given that macrophages might be one of the major target cells through which MSCs can induce their immunomodulatory effects, and that KCs (as they are essentially macrophages) are key factors in liver transplant tolerance induction, we believe that, compared with other solid-organ transplantation, liver transplantation might be more suitable for immunoregulation involving MSCs.

MSCs in Animal Models

Since animal models of solid-organ transplantation involving MSCs were reported in 2006 in heart transplantation, many reports have described using MSCs in liver transplantation^105,106. Such studies have indicated that different MSC sources, including recipients, donors, and third-parties, could all lead to liver allograft tolerance. Although some investigation results from in vitro experiments have been verified in vivo [for example, MSCs overexpressing interleukin-10 (IL-10) could lead to liver transplant tolerance in rats more effectively than normal MSC], due to their complexity, in vivo investigations are quite different from in vitro studies, and more research is needed^36,80. For example, the ratio of MSCs to T-cells or peripheral blood mononuclear cells (PBMCs), which has already been determined in in vitro studies, would mean a large number of cells in in vivo experiments, and such a large number of cells would easily cause pulmonary embolism¹⁰⁷. Thus, the approach and dose of MSC infusion are quite important in vivo investigation. The timing and methods of cell administration (pretransplant versus posttransplant) are also crucial because the infusion scheme can determine the final migratory location of MSCs, thus affecting MSC stimulation and interactions within the local environments and their immunomodulatory capacity^108,109. Although several studies have reported that MSC infusion after transplantation may lead to graft dysfunction and failure to prolong graft survival, more studies still recommended a posttransplant infusion scheme, because the posttransplant infusion scheme can promote intragraft MSC migration, which can improve MSC tissue repair properties¹¹⁰. Moreover, pretransplant infusion may limit MSC homing into grafts and promote their migration to the lungs, where they might lose viability after 24 h¹¹¹.

In most animal liver transplantation studies, liver function improvements and amelioration of inflammation can be observed in the early posttransplant phase (7 days after surgery) while anesis of liver inflammation during this phase can be attributed to the control of rejection as well as the relief of ischemia reperfusion injury (IRI)^110,112. In fact, MSCs have been regarded as a protective factor against IRI, and MSC-mediated IRI protection might be a consequence of their inherent immunosuppressive capacity, similar to inhibition of rejection¹¹³. For example, Zheng and his group proved that MSCs, through the release of anti-inflammatory factors, significantly alleviate hepatic IRI¹¹⁴. Moreover, researchers also believe that MSCs could stabilize neovascularization by inhibiting inflammation, which would improve the success rate of liver transplantation¹¹⁵. To sum up, in liver transplantation, the immunomodulatory capacity of MSCs could potentially be helpful to promote liver transplantation, reduce hepatic ischemia reperfusion injury, and control liver transplantation rejection.

MSCs in Clinical Trials

More than 10 years have passed since MSCs were first used as an immunomodulator in humans (in a patient with GVHD in 2004)¹¹⁶. To date, although several cases of MSC application in the clinic have been reported (Table 3), clinical trials with large sample sizes on liver transplantation involving MSCs are still insufficient. The reasons might lie partly in the following intrinsic constraints and obstacles in the application of MSC in clinical liver transplantation: (1) Ethical problems: after decades of development, clinical liver transplantation has become quite a safe and efficient therapy for end-stage liver diseases; thus, any alteration in clinical standards would bring about much ethical doubt. In addition, ethical issues have also contributed greatly to the delay in stem cells being brought into clinical trials in many countries or regions. (For instance, wide applications of stem cells in preclinical studies were prohibited in China until July 2015.) (2) Immune environment issues: to ensure the best survival of the liver graft, recipients generally have to be severely immunosuppressed in the induction period, which means that any additional cell therapy would encounter a condition of systemic immunosuppression and would usually meet high concentrations of pharmacological immunosuppressors that would probably influence the function of transplanted MSCs. (3) Sources and pretreatment of MSCs: although the low immunogenicity of MSCs is well known, MSCs cannot be completely immunoprivileged in vivo¹¹⁰. Moreover, it is well documented that the culture conditions and pretreatment can influence the immunomodulatory potentials of MSCs; therefore the source and pretreatment of MSCs that are chosen for clinical use need further study. (4) Timing, approach, and dosage of MSC infusion: as previously mentioned, each of these factors is quite important in MSC application; however, the experience of in vitro studies and animal experiments cannot inform clinical applications. Thus, more studies with larger animals (for example, pigs) with dose escalation should be conducted. (5) Safety concerns: due to a lack of knowledge, crucial safety concerns need to be considered, such as whether MSCs increase tumor incidence or opportunistic infections risk, similar to immunosuppressive drugs, and whether MSCs have the potential for maldifferentiation given that MSCs possess multilineage differentiation potential. On the other hand, however, due to the different types of liver diseases that warrant liver transplantation, these safety problems might not be critical in all clinical transplantation cases. For example, due to the potential risk of tumor promotion, MSCs may not be suitable for patients diagnosed with early stage liver cancer but might be feasible for the patients with liver cirrhosis.

Table 3.

Clinical Trials of Liver Transplantation Based on MSCs Carried Out Up to August 1, 2019. All Data from https://clinicaltrials.gov/ and PubMed.

Study title	NCT number	Study start date	Transplantation schemes	Sample size	Follow-up period	References	Conclusion and effectiveness analysis
Safety and feasibility of multipotent adult progenitor cells for immunomodulation therapy after liver transplantation: A phase I study of the MiSOT study consortium	NCT01841632	November 2011	Multipotent adult progenitor cells(MAPCs) Allotransplantation Dose:3× 10⁸ -1.2×10⁹ Per patient	1	6 months	^91,117	This first-in-human case study confirmed that intraportal and intravenous infusion of third-party MSCs after liver transplantation is clinically feasible. Due to the limitation of small sample size, large sample clinical trials are still needed to further verify safety and efficacy of third-party MSCs.
Human Mesenchymal Stem Cells Induce Liver	NCT01429038	February 2012	BM-MSCs Allotransplantation Dose:1.5-3×10⁶/kg	20	12 months	⁸⁹	This phase I-II, open-label, clinical study shown that no severe opportunistic infections or neoplasms were found in patients treated with MSCs, which further confirmed the safety of MSCs for liver transplantation. However, two patients had recurrence of hepatocellular carcinoma and two high-risk patients developed asymptomatic CMV, although there was no evidence that MSCs were involved, which deserved our attention. Additionally, MSC injection schemes should be optimized to benefit patients.
Human Mesenchymal Stem Cells Induce Liver Transplant Tolerance	NCT01690247	February 2012	UC-MSCs Allotransplantation Dose: 1×10⁶/kg	27	3 months	⁹²	Compared with the previous open trials, this study applied UC-MSCs and showed stronger immunomodulatory effects on liver transplantation patients, and no MSC-related complications occurred during follow up. This study supports the feasibility and clinical effects of MSCs in liver transplantation patients.
Therapeutic Strategy and the Role of Mesenchymal Stromal Cells for ABO Incompatible Liver Transplantation	NCT02706132	February 2014	–	–	–	–	Not yet published.
Mesenchymal Stem Cells Transplantation for Ischemic-type Biliary Lesions	NCT02223897	February 2012	UC-MSCs Allotransplantation Dose: 1×10⁶/kg	12	24 months	⁹⁰	The study showed that MSC infusion in patients with ischemic biliary tract disease after liver transplantation reduced the need for interventional therapy improved graft survival compared with traditional therapy and further supported the feasibility of applying MSCs for liver transplantation.
MSC Therapy in Liver Transplantation	NCT02260375	October 2014	–	–	–	–	Not yet published.
Mobilization of Mesenchymal Stem Cells During Liver Transplantation	NCT02557724	September 2015	–	–	–	–	Not yet published.
Safety and Tolerance of Immunomodulating Therapy With Donor-specific MSC in Pediatric Living Donor Liver Transplantation	NCT02957552	March 2017	–	–	–	¹¹⁸	Not yet published.

Despite the many constraints and obstacles, the application of MSCs in clinical use has not been stopped. From reports of a series of phase II clinical studies in Europe on the treatment of acute steroid-resistant GVHD, MSCs have shown substantially promising results¹¹⁶. These results not only suggest that MSCs might still be effective in GVHD even after the failure of immunosuppressive drugs, but also indicate the possibility of MSCs application in solid-organ transplantation. The MiSOT-I trial, performed by the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) organization, was initiated in 2013. To date, much feedback information regarding clinical research involving MSC application in liver and kidney transplantation has been summarized¹¹⁰. Such feedback, combined with other clinical trials of liver transplantation, includes mainly the following aspects: (1) The timing of MSC infusion: MSCs need to be used in the early posttransplantation phase because of their long-term pro-tolerogenic effects. Because of persistent chronic rejection, MSCs should be used posttransplantation if the function of the graft is stable or deteriorating. Moreover, the long-term effects of MSCs on chronic rejection are still expected. (2) Use of concomitant immunosuppression: Considering the existence of immunogenicity and drug targets of MSCs, the drug combinations used with MSCs may be a promising way to improve future clinical transplantation. (3) Sources of MSCs: all sources of MSC, including BM, adipose tissue and other human tissues share similarly high therapeutic potentials. Regarding immunogenicity, based on the outcomes of liver transplantation trials, MSCs were proven to be safe and effective. (4) Safety concerns: regarding the potential of MSC maldifferentiation, evidence for malignant transformation of MSCs was not found in all studies, but further attention is still needed. For the issue of opportunistic infections, four recent clinical trials of MSCs in liver transplantation showed no increased incidence of infection in patients after receiving MSCs^89

–92. However, given the small sample size and short follow-up period of the above-mentioned trials, and a clinical trial based by Reinders et al. on renal transplantation that described that three of six patients infused with MSCs had opportunistic but mild viral infections, the possibility of infection after MSC injection should still be taken seriously⁸⁷. (5) Immunoregulation results: Although MSCs were proven to be effective in alloimmune reaction treatments by a large number of in vivo and in vitro experiments, a clinical trial on liver transplantation above mentioned lacked the protective effects of MSCs in patients with liver transplantation, and, after withdrawal of the immunosuppressive agents, immunological rejection occurred successively in MSC-treated patients and disappeared after resumption of the immunosuppressive agents⁸⁹. This result was most likely due to the choice of immunosuppressants and MSCs; and an inappropriate application scheme of MSCs. Another clinical trial of liver transplantation showed that, in comparison to using immunosuppressive drugs alone, MSCs could better improve liver tissue, and were able to regulate the proportion of T lymphocyte subsets to promote immune tolerance during the acute rejection phase after liver transplantation. However, the long-term status of patients could not be observed, due to the short follow-up period of only 12 weeks⁹². For induction therapy, although no clinical trials related to liver transplantation have been reported, two clinical trials on kidney transplantation confirmed the safety of MSCs as induction therapy for organ transplantation^119,120. Moreover, one of the above studies showed that MSCs were superior to IL-2 for induction therapy¹²⁰.

Concerning liver transplantation, specifically, information on MSC application in clinical liver surgery is still lacking. The available information on MSC application in liver transplantation is encouraging; however, large-scale trials are still needed. Nevertheless, the experience of researchers in the design of investigations is still helpful and meaningful for subsequent studies.

MSCs Combined with Immunosuppressive Drugs in Liver Transplantation

At present, there is a consensus on the use of calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporine, as immune maintenance drugs after liver transplantation, supplemented with antimetabolites such as acetazolamide (AZA) and mycophenolic acid (MPA), or m-TOR inhibitors to achieve a lower dose of CNI and alleviate side effects¹²¹. Glucocorticoids, interleukin-2 and antithymosin are recommended for induction therapy of liver transplantation¹²¹. Previous clinical studies on liver transplantation are also based on the application of MSCs combined with tacrolimus and mycophenolate mofetil (MMF) in the immune maintenance therapy of liver transplantation patients. Given the low immunogenicity of MSCs, and given that there are still targets on which immunosuppressive drugs act, this issue should be considered when developing a combination regimen of MSCs and immunosuppressive drugs¹²².

It was found that short-term exposure to immunosuppressive agents in vitro had no toxicity and did not induce apoptosis in MSCs, but long-term exposure to tacrolimus at high doses for 7 days could significantly promote the death of MSCs¹²². Even exposure to MPA and rapamycin at therapeutic doses inhibited the proliferation of MSCs¹²². These results suggested that short-term and low-dose immunosuppressive agents combined with MSCs seemed to achieve better results in patients undergoing liver transplantation. In addition, the added protective agents seemed to be effective in reducing the toxicity of immunosuppressants on MSCs. For example, combination with oxytocin counteracted the cytotoxicity of tacrolimus on MSCs¹²³. Researchers also found that different kinds of immunosuppressants have heterogeneous interaction effects with MSCs. For CNIs, MSCs combined with tacrolimus demonstrated considerable coordination in immune regulation after organ transplantation. Kuo et al. found that MSCs plus tacrolimus improved graft survival in a miniature swine hind-limb model¹²⁴. Suda and his group also showed that the combination of MSCs and tacrolimus could relieve ischemic brain damage in rats¹²⁵. A prospective, nonrandomized study on kidney transplantation proved that the use of MSCs could offset the dose of tacrolimus used in patients without increasing the risk of rejection, and indicated that combined use with MSCs could decrease tacrolimus dosage and thus alleviate adverse reactions in organ transplantation patients¹²⁶. However, the synergistic effects of tacrolimus combined with MSCs on immune regulation have been controversial in some in vitro studies. Poncelet et al. reported that MSCs cocultured with tacrolimus effectively increased the inhibitory effect on T cells¹²⁷, but Buron et al. showed an antagonistic effect of MSCs and tacrolimus on T cell inhibition¹²⁸. This may be attributed to the difference in the origin of the MSCs in the above-mentioned studies. Cyclosporine was also found to interact with MSCs. Some studies have shown that cyclosporine synergistically promotes immunosuppression with MSCs¹²⁹. However, some studies have found that cyclosporine and MSCs have antagonistic effects, which may be attributed to the differences in experimental treatment methods, such as lymphocyte stimulation, and the basic condition of the experimental subjects¹²⁸. Exhilaratingly, MMF/MPA showed better synergistic immunosuppressive action with MSCs than other immunosuppressive drugs in both in vitro and in vivo studies. For example, a study showed that MSCs combined with MMF could significantly increase heart transplant survival compared with single-use MSCs or MSCs combined with CNIs in a rat model¹³⁰. In an in vitro study, MSCs combined with MPA showed stronger inhibitory effects on lymphocyte proliferation than CNIs, m-TOR inhibitors, and dexamethasone¹²⁸. These studies seemed to suggest that MMF/MPA was more suitable for combined use with MSCs than other immunosuppressants. Additionally, both steroid hormones and m-TOR inhibitors also exhibited synergistic immunosuppressive effects with MSCs in animal models^131,132. Given the potential role of MSCs in liver transplantation, these effects should be further studied and considered when formulating a compatibility program for liver transplantation patients¹³². Taken together, the above findings imply that multiple combination regimens based on MSCs could be designed as induction or maintenance therapies for liver transplant patients with different disease conditions in the future.

Potential Therapeutic Properties of MSCs in Liver Transplantation

In addition to posttransplant immunosuppression, MSCs are also able to promote liver regeneration, angiogenesis, and anti-fibrosis, which are potentially helpful for liver transplantation in patients (Figure 3). For liver regeneration, studies found that MSCs could promote liver reparation after partial hepatectomy in mice with hepatic steatosis (HS)¹³³. MSCs that increased angiogenesis in an animal model of acute liver failure and that relieve hepatic cirrhosis in animal and clinical trials were also found^134
–136. Cytokines and factors secreted by MSCs through the paracrine pathway appear to play a major role in these processes. For example, MSCs could secrete cytokines such as IL-6, hepatocyte growth factor (HGF), and IGFBP-2 to promote hepatocyte regeneration and inhibit hepatocyte apoptosis. Metalloproteinase (MMPs) and insulin growth factor-like-I (IGF-I) released by MSCs could effectively reduce collagen accumulation and counter liver fibrosis^137,138. MSCs were able to secrete various angiogenic factors to promote angiogenesis. Molecules such as VEGF-A, VWF, SDF-1α, Cyr61, MMP2, and MMP9 are involved in this process^139

–142. In addition, MSCs can also participate in these processes by regulating the immune response and inhibiting the release of inflammatory factors¹⁴³. Moreover, studies show that overexpression of related cytokines such as HGF, in MSCs can alleviate liver function damage, reduce liver fibrosis, and improve graft survival compared with normal MSCs^67
–69. These studies suggest that MSCs have potential therapeutic properties in liver transplantation, and looking for ways to enhance these properties of MSCs and thereby enhance the effect of MSCs on liver transplantation seems to be a promising approach but it still needs be further evaluated in clinical trials.

Figure 3.

MSCs promote liver regeneration, angiogenesis and count fibrosis by secreting cytokines and exosomes, regulating inflammation and differentiation.

Despite their immunomodulatory capacity as a multipotent stem cells, MSCs have multidirectional differentiation characteristics. In previous studies, researchers proved that MSCs could differentiate into pericytes and vascular cells in vivo¹³⁹. It should be mentioned that MSCs have the potential to differentiate into hepatocyte-like cells both in vitro and vivo^137,144. Hepatocyte-like cells derived from MSCs have gene expression profiles similar to those of hepatocytes and perform several hepatocyte-like functions that promote the recovery of damaged liver function. These studies show a potential mechanism for MSCs to help patients undergoing liver transplantation. However, given that the immune regulation of MSCs is impaired during the process of differentiating into hepatocyte-like cells, it seems unwise to only pursue the promotion of differentiation of MSCs into hepatocytes in the application of liver transplantation.

Exosomes, as a type of extracellular vesicle (EV) are defined as lipid bilayer particles 20–150 nm in diameter released by various cells¹⁴⁵. Despite being initially regarded as a waste product of cell rejection, exosomes, which are rich in proteins, coding and non-coding RNA, and even DNA, are closely associated with many diseases and physiological processes, and have attracted the attention of researchers in recent years. Given that exosomes from MSCs display powerful physiological regulatory functions, have lower ethical considerations and immunogenicity compared with stem cell therapy, and have no increased risk of cancer, they seem to be a promising approach to acellular therapy. For liver transplantation, exosomes released from MSCs have been proven to have immune regulation, tissue repair and angiogenesis functions similar to those of source cells. One study showed that injecting exosomes derived from BM-MSCs into rats with GVHD every week could inhibit Th17 cells and Tregs, and enhance pathological conditions¹⁴⁶. Liver fibrosis was also alleviated after transplantation of MSC-derived exosomes by reducing oxidative stress and inhibiting hepatocyte apoptosis in a liver injury model induced by CCL4¹⁴⁷. Whole-body administration of exosomes derived from MSCs promoted liver repair and angiogenesis in damaged areas^148,149. In addition, a study showed that injecting MSC-derived exosomes into mice with hepatocellular carcinoma could effectively inhibit tumor growth and enhance chemosensitivity due to the abundance of anti-tumor microRNAs in the exosomes¹⁵⁰. This study indicated that exosomes derived from MSCs may be particularly suitable for liver transplantation patients with malignant tumors, though the actual effects still need to be measured further by clinical trials. Together, exosomes derived from MSCs can be used not only as a potential mechanism for explaining the effect of MSCs on liver transplantation, but also as a new tool that may be used to benefit patients undergoing liver transplantation at some future date.

Conclusions

According to the available information from investigations including in vitro, animal, and phase I and II clinical studies, MSC infusion is generally feasible and safe for liver transplantation, but we suggest the need for a cautious approach for certain types of patients, such as patients with tumors. The application of MSCs could promote immune tolerance in patients with liver transplantation; however, whether MSCs could replace immunosuppressive drugs is questionable.

Due to the heterogeneity of MSCs, it is clear that the immunoregulatory function of MSCs can be improved by choosing appropriate sources, providing feasible pretreatment, compatible with practicable immunosuppressants and gene modification; however, whether the above schemes are actually beneficial for liver transplant patients without increasing the risk of complications, and even help to completely replace immunosuppressive drugs, still requires further clinical trial verification. It is known that soluble molecules, exosomes and direct cell-to-cell contact are considered to be the main ways whereby MSCs exert their immunosuppressive effects, but the exact mechanisms of immune regulation are not yet fully understood. Additionally, exosomes show promising therapeutic prospects, but whether exosomes can replace cell therapy in liver transplantation needs further confirmation. The MSC characteristics of promoting liver regeneration, angiogenesis, and alleviating liver fibrosis are helpful for liver transplantation patients. Improving these properties of MSCs may better benefit liver transplantation patients. The ability of MSCs to undergo multidirectional differentiation is also involved in these processes. However, it remains unclear whether regulating the differentiation of MSCs can benefit liver transplant recipients.

In summary, MSC-based therapy is a promising treatment for liver transplantation, but the exact mechanisms and effects of MSCs on liver transplantation, as well as the problems that might be encountered in the clinical applications, still require further study; such studies will greatly aid the future clinical use of MSCs in liver transplantation.

Footnotes

Author Notes

Yu You and Di-guang Wen contributed equally to this work.

Author Contributions

YY, WDG, and LZJ performed research and wrote the first draft. GJP collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LZJ is the guarantor.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by the National Science Foundation of China (No. 81170442, 81470899, 81702357), National Scholarship Foundation (No.201208505116), and Outstanding young talent fund of the second hospital of CQMU (2011).

ORCID iD

Zuo-jin Liu

References

Chascsa

Vargas

. The gastroenterologist’s guide to management of the post-liver transplant patient. Am J Gastroenterol. 2018;113(6):819–28.

Durand

Levitsky

Cauchy

Gilgenkrantz

Soubrane

Francoz

. Age and liver transplantation. J Hepatol. 2019;70(4):745–58.

Bottomley

Harden

. Update on the long-term complications of renal transplantation. Br Med Bull. 2013;106:117–34.

Casiraghi

Perico

Cortinovis

Remuzzi

. Mesenchymal stromal cells in renal transplantation: opportunities and challenges. Nat Rev Nephrol. 2016;12(4):241–53.

Hinden

Shainer

Almogi-Hazan

. Ex Vivo induced regulatory human/murine mesenchymal stem cells as immune modulators. Stem Cells. 2015;33(7):2256–67.

Wang

Mei

Wang

Cheng

. Human adipose mesenchymal stem cells show more efficient angiogenesis promotion on endothelial colony-forming cells than umbilical cord and endometrium. Stem Cells Int. 2018;2018:7537589.

Lim

Ryu

Lee

Park

Min

. Mesenchymal stem cells (MSCs) attenuate cutaneous sclerodermatous graft-versus-host disease (Scl-GVHD) through inhibition of immune cell infiltration in a mouse model. J Invest Dermatol. 2017;137(9):1895–904.

Cortés-Araya

Amilon

Rink

Black

Lisowski

Donadeu

Esteves

. Comparison of antibacterial and immunological properties of mesenchymal stem/stromal cells from equine bone marrow, endometrium, and adipose tissue. Stem Cells Dev. 2018;27(21):1518–25.

Peng

Chen

Liu

Zhang

Huang

Liu

Zhou

Huang

Fan

Sun

, et al. Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. Leukemia. 2015;29(3):636–46.

10.

Abumaree

Abomaray

Alshehri

Almutairi

AlAskar

Kalionis

Al Jumah

. Phenotypic and functional characterization of mesenchymal stem/multipotent stromal cells from decidua parietalis of human term placenta. Reprod Sci. 2016;23(9):1193–207.

11.

Bourebaba

Michalak

Röcken

Marycz

. Cladophora glomerata methanolic extract decreases oxidative stress and improves viability and mitochondrial potential in equine adipose derived mesenchymal stem cells (ASCs). Biomed Pharmacother. 2018;111:6–18.

12.

Sivan

Jayakumar

Krishnan

. Matrix-directed differentiation of human adipose-derived mesenchymal stem cells to dermal-like fibroblasts that produce extracellular matrix. J Tissue Eng Regen Med. 2016;10(10):E546–58.

13.

Bana

Sanooghi

Soleimani

Hayati Roodbari

Alavi Moghaddam

Joghataei

Sayahpour

Faghihi

. A comparative study to evaluate myogenic differentiation potential of human chorion versus umbilical cord blood-derived mesenchymal stem cells. Tissue Cell. 2017;49(4):495–502.

14.

Shi

Wang

Liu

Hou

Shao

Wang

. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14(8):493–507.

15.

Fujita

Kawamoto

. Stem cell-based peripheral vascular regeneration. Adv Drug Deliv Rev. 2017;120:25–40.

16.

Ren

Zhang

Zhao

Ling

L’huillie

Zhang

Roberts

Zhang

, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells. 2009;27(8):1954–62.

17.

Chi

Yang

Cui

Song

Yang

Han

. Heterogeneity of proangiogenic features in mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, and placenta. Stem Cell Res Ther. 2016;7(1):163.

18.

Rajeshkumar

Agrawal

Rashighi

Saidi

. Mesenchymal stem cells and co-stimulation blockade enhance bone marrow engraftment and induce immunological tolerance. Int J Organ Transplant Med. 2015;6(2):55–60.

19.

Barberini

Aleman

Aristizabal

Spriet

Clark

Walker

Galuppo

Amorim

Woolard

Borjesson

. Safety and tracking of intrathecal allogeneic mesenchymal stem cell transplantation in healthy and diseased horses. Stem Cell Res Ther. 2018;9(1):96.

20.

Di Nicola

Carlo-Stella

Magni

Milanesi

Longoni

Matteucci

Grisanti

Gianni

. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.

21.

Kaundal

Bagai

Rakha

. Immunomodulatory plasticity of mesenchymal stem cells: a potential key to successful solid organ transplantation. J Transl Med. 2018;16(1):31.

22.

Ock

Baregundi Subbarao

Lee

Jeon

Lee

Park

Hwang

Rho

. Comparison of immunomodulation properties of porcine mesenchymal stromal/stem cells derived from the bone marrow, adipose tissue, and dermal skin tissue. Stem Cells Int. 2016;2016:9581350.

23.

Rafat

Mohammadi Roushandeh

Alizadeh

Hashemi-Firouzi

Golipoor

. Comparison of the melatonin preconditioning efficacy between bone marrow and adipose-derived mesenchymal stem cells. Cell J. 2019;20(4):450–58.

24.

Zhuang

Shi

. Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells. Mol Med Rep. 2015;11(1):166–74.

25.

Che

Zhou

Liu

Shi

Sun

. Umbilical cord mesenchymal stem cells suppress B-cell proliferation and differentiation. Cell Immunol. 2012;274(1–2):46–53.

26.

Rosado

Bernardo

Scarsella

Conforti

Giorda

Biagini

Cascioli

Rossi

Guzzo

Vivarelli

Dello Strologo

, et al. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev. 2015;24(1):93–103.

27.

Corcione

Benvenuto

Ferretti

Giunti

Cappiello

Cazzanti

Risso

Gualandi

Mancardi

Pistoia

Uccelli

. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367–72.

28.

Vitacolonna

Schubert

Herbert

Taubert

Singh

Zöller

. Improved T and B cell recovery by the transfer of slowly dividing human hematopoietic stem cells. Leuk Res. 2010;34(5):622–30.

29.

Thomas

Jäger

Mauel

Brandau

Lask

Flohé

. Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm. 2014;2014:143463.

30.

Castro-Manrreza

Montesinos

. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res. 2015;2015:394917.

31.

Park

Kim

Ryu

Woo

Ryu

. Immune suppressive effects of tonsil-derived mesenchymal stem cells on mouse bone-marrow-derived dendritic cells. Stem Cells Int. 2015;2015:106540.

32.

Eom

Kim

Park

Kim

Cho

. Regulatory dendritic cells induced by mesenchymal stem cells ameliorate dextran sodium sulfate-induced chronic colitis in mice. Gut Liver. 2018;12(6):664–73.

33.

Khosravi

Bidmeshkipour

Moravej

Hojjat-Assari

Naserian

Karimi

. Induction of CD4+CD25+Foxp3+ regulatory T cells by mesenchymal stem cells is associated with RUNX complex factors. Immunol Res. 2018;66(1):207–18.

34.

Wang

Zhang

Zhao

Xue

Zhang

Luan

. Human placenta-derived mesenchymal stem cells ameliorate GVHD by modulating Th17/Tr1 balance via expression of PD-L2. Life Sci. 2018;214:98–105.

35.

Khosravi

Bidmeshkipour

Cohen

Moravej

Hojjat-Assari

Naserian

Karimi

. Induction of CD4+CD25+FOXP3+ regulatory T cells by mesenchymal stem cells is associated with modulation of ubiquitination factors and TSDR demethylation. Stem Cell Res Ther. 2018;9(1):273.

36.

You

Zhang

Gong

Chen

Yang

Liu

. Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance. Immunol Res. 2015;62(3):292–305.

37.

Liu

Lin

Huang

Wei

. Bone marrow mesenchymal stem cells suppressing activation of allogeneic cytokine-induced killer/natural killer cells either by direct or indirect interaction. Cell Biol Int. 2015;39(4):435–45.

38.

Rong

Liu

Yao

Jiang

Wang

Xie

. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway. Stem Cell Res Ther. 2019;10:98.

39.

Leng

Zhao

Gao

Jin

Lian

Yan

Xia

Zhuang

, et al. Human iPSC-MSC-derived xenografts modulate immune responses by inhibiting the cleavage of caspases. Stem Cells. 2017;35(1):1719–32.

40.

Laing

Fanelli

Ramirez-Valdez

Lechler

Lombardi

Sharpe

. Mesenchymal stem cells inhibit T-cell function through conserved induction of cellular stress. PLoS One. 2019;14(3):e0213170.

41.

Wang

Guo

Zhang

Chen

Tian

Xie

Jiang

. Exosomal sphingosine 1-phosphate secreted by mesenchymal stem cells regulated Treg/Th17 balance in aplastic anemia. IUBMB Life. 2019;71(9):1284–92.

42.

Liu

Qiu

Deng

Jin

. Influence of TNF-α on the immunomodulatory property of laryngeal mucosa mesenchymal stromal cells’ [in Chinese]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2019;54(3):203–08.

43.

Chiesa

Morbelli

Morando

Massollo

Marini

Bertoni

Frassoni

Bartolomé

Sambuceti

Traggiai

Uccelli

. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci U S A. 2011;108(42):17384–89.

44.

Ghosh

Barik

Bhuniya

Dhar

Dasgupta

Ghosh

Sarkar

Guha

Sarkar

Chakrabarti

Saha

, et al. Tumor-associated mesenchymal stem cells inhibit naïve T cell expansion by blocking cysteine export from dendritic cells. Int J Cancer. 2016;139(9):2068–81.

45.

Kim

Jung

Cho

Choi

Lee

Kim

Lee

. Immunomodulatory effects of placenta-derived mesenchymal stem cells on t cells by regulation of FoxP3 expression. Int J Stem Cells. 2018;11(2):196–204.

46.

Crain

Robinson

Thane

Davis

Meola

Barton

Yang

Hoffman

. Extracellular vesicles from wharton’s jelly mesenchymal stem cells suppress CD4 expressing T cells through transforming growth factor beta and adenosine signaling in a canine model. Stem Cells Dev. 2019;28(3):212–26.

47.

Liang

Jiang

Yao

Wang

Chen

Zhou

Zhai

Feng

Han

. Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro. Hematology. 2018;23(1):44–49.

48.

Xie

Zhou

Yan

. Exosomes derived from IDO1-Overexpressing rat bone marrow mesenchymal stem cells promote immunotolerance of cardiac allografts [published online ahead of print October 12, 2018]. Cell Transplant. 2018;963689718805375.

49.

Miyagawa

Nakayamada

Nakano

Yamagata

Sakata

Yamaoka

Tanaka

. Induction of regulatory T cells and its regulation with insulin-like growth factor/insulin-like growth factor binding protein-4 by human mesenchymal stem cells. J Immunol. 2017;199(5):1616–25.

50.

Wang

Tang

Ding

Shi

. Mesenchymal stem cells increase heme oxygenase 1-activated autophagy in treatment of acute liver failure. Biochem Biophys Res Commun. 2019;508(3):682–89.

51.

Song

Kim

Yang

Ryu

Nam

Bhang

Jung

Youn

. Prostaglandin E2 secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. BMC Vet Res. 2018;14(1):354.

52.

Nahar

Nakashima

Miyagi-Shiohira

Kinjo

Toyoda

Kobayashi

Saitoh

Watanabe

Noguchi

Fujita

. Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease. World J Stem Cells. 2018;10(11):146–59.

53.

Lee

Kim

Park

Lee

Kim

Chang

Bae

Kim

Hong

, et al. CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms. Sci Rep. 2017;7:41258.

54.

Reesink

Sutton

Shurer

Peterson

Tan

Paszek

Nixon

. Galectin-1 and galectin-3 expression in equine mesenchymal stromal cells (MSCs), synovial fibroblasts and chondrocytes, and the effect of inflammation on MSC motility. Stem Cell Res Ther. 2017;8(1):243.

55.

Hong

Lim

Chung

Kang

Kim

Roh

Lew

. Immune tolerance of human dental pulp-derived mesenchymal stem cells mediated by CD4⁺CD25⁺FoxP3⁺ regulatory T-cells and induced by TGF-β1 and IL-10. Yonsei Med J. 2017;58(5):1031–39.

56.

Willis

Fernandez-Gonzalez

Reis

Mitsialis

Kourembanas

. Macrophage immunomodulation: the gatekeeper for mesenchymal stem cell derived-exosomes in pulmonary arterial hypertension. Int J Mol Sci. 2018;19(9):E2534.

57.

Németh

Leelahavanichkul

Yuen

Mayer

Parmelee

Doi

Robey

Leelahavanichkul

Koller

Brown

, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine. 2009;15(1):42–49.

58.

Liang

Zhang

Kong

Deng

Wang

Feng

Zhao

Hua

Wang

Sun

. Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study. Stem Cell Res Ther. 2018;9(1):312.

59.

Daneshmandi

Karimi

Pourfathollah

. TGF-β engineered mesenchymal stem cells (TGF-β/MSCs) for treatment of Type 1 diabetes (T1D) mice model. Int Immunopharmacol. 2017;44:191–96.

60.

Llufriu

Sepúlveda

Blanco

Marín

Moreno

Berenguer

Gabilondo

Martínez-Heras

Sola-Valls

Arnaiz

Andreu

, et al. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One. 2014;9(12):e113936.

61.

Blazar

MacDonald

Hill

. Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood. 2018;131(24):2651–60.

62.

Zhang

Chen

Bie

. Bone marrow-derived mesenchymal stem cells as immunosuppressants in liver transplantation: a review of current data. Transfus Med Rev. 2012;26(2):129–41.

63.

Wang

Liu

Qian

Zhang

Peng

. The study on immunomodulation of donor mesenchymal stem cells on discordant liver xenotransplantation [in Chinese]. Zhonghua Wai Ke Za Zhi Zhonghua Wai Ke Za Zhi. 2005;43(19):1254–58.

64.

Wan

Cheng

Wang

Liu

. Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model. Hepatobiliary Pancreat Dis Int. 2008;7(1):29–33.

65.

Hong

Huang

Yin

Zhao

Wang

. Immunosuppressive function of bone marrow mesenchymal stem cells on acute rejection of liver allografts in rats. Transplant Proc. 2009;41(1):403–9.

66.

Pan

Hou

Zhang

Gong

Cheng

Jian

Gao

. Infusion of autologous mesenchymal stem cells prolongs the survival of dogs receiving living donor liver transplantation [in Chinese]. Nan Fang Yi Ke Da Xue Bao. 2009;29(9):1783–86.

67.

Qian

Chen

Yao

Zhang

Kong

Sun

Wang

. Antifibrotic effect of hepatocyte growth factor-expressing mesenchymal stem cells in small-for-size liver transplant rats. Stem Cells Dev. 2010;19(6):903–14.

68.

Yao

Chen

Fan

Sun

Wang

. Mesenchymal stem cells over-expressing hepatocyte growth factor improve small-for-size liver grafts regeneration. Mol Ther. 2007;15(7):1382–89.

69.

Zhu

Chen

. Effect of human hepatocyte growth factor gene-modified bone marrow mesenchymal stem cells on immunological rejection after allograft liver transplantation in rats [in Chinese]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011;25(7):871–76.

70.

Sun

Wen

Wang

. Immunological effect induced by mesenchymal stem cells in a rat liver transplantation model. Exp Ther Med. 2015;10(2):401–06.

71.

Xia

Chen

Liu

Liang

Bai

Zhang

Liang

. Mesenchymal stem cells administered after liver transplantation prevent acute graft-versus-host disease in rats. Liver Transpl. 2012;18(6):696–706.

72.

Wang

Zhang

Xie

Zheng

. Bone marrow-derived mesenchymal stem cells inhibit acute rejection of rat liver allografts in association with regulatory T-cell expansion. Transplant Proc. 2009 41(10):4352–56.

73.

Tang

Yang

Yao

Yin

Nyberg

Wang

. Transforming growth factor-β-expressing mesenchymal stem cells induce local tolerance in a rat liver transplantation model of acute rejection. Stem Cells. 2016;34(11):2681–92.

74.

Shen

Liu

Yang

Yin

Zheng

Zhang

Song

. Immunomodulatory effects of bone marrow mesenchymal stem cells overexpressing heme oxygenase-1: protective effects on acute rejection following reduced-size liver transplantation in a rat model. Cell Immunol. 2017,313:10–24.

75.

Wang

Shen

Yang

Yin

Zheng

Liu

Song

. Protective effects of heme oxygenase-1-transduced bone marrow-derived mesenchymal stem cells on reduced size liver transplantation: role of autophagy regulated by the ERK/mTOR signaling pathway. Int J Mol Med. 2017;40(5):1537–48.

76.

Song

Yang

Yin

Zhang

Cao

Dong

Shen

. Improvement of liver transplantation outcome by heme oxygenase-1-transduced bone marrow mesenchymal stem cells in rats. Stem Cells Int. 2016;2016:9235073.

77.

Sasajima

Miyagi

Kakizaki

Kamei

Unno

Satomi

Goto

. Cytoprotective effects of mesenchymal stem cells during liver transplantation from donors after cardiac death in rats. Transplant Proc. 2018;50(9):2815–20.

78.

Tian

Wang

Ding

Sun

Zhang

Wang

Xie

Yan

Zheng

. Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation. Stem Cell Res Ther. 2016;7(1):157.

79.

Wang

Yan

Shi

Zhang

Peng

. Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: involvement of C-Jun N-terminal kinase, cyclin D1, and NF-κB. PLoS One. 2014;9(12):e112532.

80.

Niu

Yue

Song

Zhang

Wang

Liu

Shen

. Prevention of acute liver allograft rejection by IL-10-engineered mesenchymal stem cells. Clin Exp Immunol. 2014;176(3):473–84.

81.

Chen

Goto

Hsu

Lin

Nakano

Lai

Chang

Weng

Kuo

Wang

Cheng

, et al. Identification of miR-27b as a novel signature from the mRNA profiles of adipose-derived mesenchymal stem cells involved in the tolerogenic response. PLoS One. 2013;8(4):e60492.

82.

Wei

Yan

Han

Zhang

Peng

Liu

. Mesenchymal stem cells overexpressing C-X-C chemokine receptor type 4 improve early liver regeneration of small-for-size liver grafts. Liver Transpl. 2013;19(2):215–225.

83.

Jia

Zeng

Zhao

. The effects of local administration of mesenchymal stem cells on rat corneal allograft rejection. BMC Ophthalmol. 2018;18(1):139.

84.

Treacy

O’Flynn

Ryan

A. E

Morcos

Lohan

Schu

Wilk

Fahy

Griffin

Nosov

Ritter

. Mesenchymal stem cell therapy promotes corneal allograft survival in rats by local and systemic immunomodulation. Am J Transplant. 2014;14(9):2023–36.

85.

Zhang

Jiang

Liang

Liao

Zhang

Yue

Chiu

Chai

Liang

, et al. iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy. Stem Cell Reports. 2016;7(4):749–63.

86.

Reinders

de Fijter

Roelofs

Bajema

de Vries

Schaapherder

Claas

van Miert

Roelen

van Kooten

Fibbe

, et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med. 2013;2(2):107–11.

87.

Perico

Casiraghi

Introna

Gotti

Todeschini

Cavinato

Capelli

Rambaldi

Cassis

Rizzo

Cortinovis

, et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011;6(2):412–22.

88.

Reinders

Dreyer

Bank

Roelofs

Heidt

Roelen

Zandvliet

Huurman

Fibbe

van Kooten

Claas

, et al. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study. J Transl Med. 2015;13:344.

89.

Detry

Vandermeulen

Delbouille

Somja

Bletard

Briquet

Lechanteur

Giet

Baudoux

Hannon

Baron

, et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I-II, open-label, clinical study. J Hepatol. 2017;67(1):47–55.

90.

Zhang

Liu

Wang

Jiang

Wang

Zhang

, et al. Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation. Cytotherapy. 2017;19(2):194–99.

91.

Soeder

Loss

Johnson

Hutchinson

Haarer

Ahrens

Offner

Deans

Van Bokkelen

Geissler

Schlitt

, et al. First-in-human case study: multipotent adult progenitor cells for immunomodulation after liver transplantation. Stem Cells Transl Med. 2015;4(8):899–904.

92.

Shi

Liu

Wang

Sun

Zhang

Wang

Meng

Jin

, et al. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection. Stem Cells Transl Med. 2017;6(12):2053–61.

93.

Blau

Daley

. Stem cells in the treatment of disease. N Engl J Med. 2019;380(18):1748–60.

94.

Lee

Song

Shin

Kim

Lee

Cho

Lee

Park

Ahn

Yang

, et al. Enhanced effect of human mesenchymal stem cells expressing human TNF-αR-Fc and HO-1 gene on porcine islet xenotransplantation in humanized mice. Xenotransplantation. 2018;25(1): e12342.

95.

Lee

Moon

Hwang

Ahn

Kim

Song

Jung

Park

Jung

. Liver transplantation in Korea: past, present, and future. Transplant Proc. 2015;47(3):705–08.

96.

Levitsky

Feng

. Tolerance in clinical liver transplantation. Hum Immunol. 2018;79(5): 283–87.

97.

Branco

Morbey

Martins

Barroso

. Tolerance after liver transplantation: where are we. Liver Transpl. 2018;24(9):1303–04.

98.

Huang

Zhou

Xia

. Innate immune cells in immune tolerance after liver transplantation. Front Immunol. 2018;9:2401.

99.

Xia

Guo

Wang

Cao

. Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance. Blood. 2008;112(8):3175–85.

100.

Fahrner

Dondorf

Ardelt

Settmacher

Rauchfuss

. Role of NK, NKT cells and macrophages in liver transplantation. World J Gastroenterol 2016;22(27):6135–44.

101.

Krenkel

Tacke

. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21.

102.

Callery

Kamei

Flye

. Kupffer cell blockade inhibits induction of tolerance by the portal venous route. Transplantation. 1989;47(6):1092–94.

103.

Sun

Meng

Huang

Zhang

. Macrophage phenotype in liver injury and repair. Scand J Immunol. 2017;85(3):166–74.

104.

Chen

Liu

Liang

Luan

Long

Chen

Peng

Yan

Gong

. Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats. Liver Transpl. 2008;14(6):823–36.

105.

Zhou

Sun

Cui

Zhu

Liu

Zhang

. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft. Transplant Proc. 2006;38(9):3046–51.

106.

Sun

Zhang

Yin

Wang

Xie

. Role of bone marrow mesenchymal stem cells with CTLA4Ig and CD40LIg gene modification in rejection reaction after liver transplantation [in Chinese]. Zhonghua Gan Zang Bing Za Zhi. 2018;26(1):54–9.

107.

Mäkelä

Takalo

Arvola

Haapanen

Yannopoulos

Blanco

Ahvenjärvi

Kiviluoma

Kerkelä

Nystedt

Juvonen

, et al. Safety and biodistribution study of bone marrow-derived mesenchymal stromal cells and mononuclear cells and the impact of the administration route in an intact porcine model. Cytotherapy. 2015;17(4):392–402.

108.

Braid

Wood

Wiese

Ford

. Intramuscular administration potentiates extended dwell time of mesenchymal stromal cells compared to other routes. Cytotherapy. 2018;20(2):232–44.

109.

Park

Ahn

Sung

Ahn

Chang

. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res. 2018;83(1–2):214–22.

110.

Franquesa

Hoogduijn

Reinders

Eggenhofer

Engela

Mensah

Torras

Pileggi

van Kooten

Mahon

Detry

, et al. Mesenchymal stem cells in solid organ transplantation (MiSOT) fourth meeting: lessons learned from first clinical trials. Transplantation. 2013;96(3):234–38.

111.

Obermajer

Popp

Johnson

Benseler

Dahlke

. Rationale and prospects of mesenchymal stem cell therapy for liver transplantation. Curr Opin Organ Transplant. 2014;19:60–4.

112.

Saidi

Rajeshkumar

Shariftabrizi

Bogdanov

Zheng

Dresser

Walter

. Human adipose-derived mesenchymal stem cells attenuate liver ischemia-reperfusion injury and promote liver regeneration. Surgery. 2014;156(5):1225–31.

113.

Bai

Zhang

Bai

Zhang

Cai

Bai

Feng

Sun

Chen

. IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway. Kidney Int. 2018;93(4):814–25.

114.

Zheng

Huang

Cai

Chen

Zhou

Zhang

Yao

J, Yang Y

Yang

. Preconditioning of umbilical cord-derived mesenchymal stem cells by rapamycin increases cell migration and ameliorates liver ischaemia/reperfusion injury in mice via the CXCR4/CXCL12 axis. Cell Prolif. 2019;52(2):e12546.

115.

Bronckaers

Hilkens

Martens

Gervois

Ratajczak

Struys

Lambrichts

. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther. 2014;143(2):181–96.

116.

Le Blanc

Rasmusson

Sundberg

Götherström

Hassan

Uzunel

Ringdén

. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439–41.

117.

Popp

Fillenberg

Eggenhofer

Renner

Dillmann

Benseler

Schnitzbauer

Hutchinson

Deans

Ladenheim

Graveen

, et al. Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I). J Transl Med. 2011;9:124.

118.

Hartleif

Schumm

Döring

Mezger

Lang

Dahlke

Riethmüller

Königsrainer

Handgretinger

Nadalin

Sturm

. Safety and tolerance of donor-derived mesenchymal stem cells in pediatric living-donor liver transplantation: the MYSTEP1 study. Stem Cells Int. 2017;2017:2352954.

119.

Sun

Huang

Han

Zhao

Cao

Zhao

Hong

Miao

. Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trial. J Transl Med. 2018;16(1):52.

120.

Tan

Liao

Zheng

Messinger

Sun

Chen

Yang

Cai

Gao

, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012;307(11):1169–77.

121.

Charlton

Levitsky

Aqel

O'Grady

Hemibach

Rinella

Fung

Ghabril

Thomason

Burra

Little

, et al. International liver transplantation society consensus statement on immunosuppression in liver transplant recipients. Transplantation. 2018;102(5):727–43.

122.

Hoogduijn

Crop

Korevaar

Peeters

Eijken

Maat

Balk

Weimar

Baan

. Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin. Transplantation. 2008;86(9):1283–91.

123.

Sir

Goker Bagca

Yigitturk

Cavusoglu

Biray Avci

Gunduz

Uyanikgil

. Antagonistic effect of oxytocin and tacrolimus combination on adipose tissue - derived mesenchymal stem cells: antagonistic effect of oxytocin and tacrolimus. Biomed Pharmacother. 2018;97:1173–81.

124.

Kuo

Chen

Chien

. Recipient adipose-derived stem cells enhance recipient cell engraftment and prolong allotransplant survival in a miniature swine hind-limb model. Cell Transplant. 2017;26(8):1418–27.

125.

Ikeguchi

Kakinoki

Ohta

Oda

Yurie

Kaizawa

Mitsui

Aoyama

Toguchida

Matsuda

. Recipient bone marrow-derived stromal cells prolong graft survival in a rat hind limb allotransplantation model. Microsurgery. 2017;37(6):632–40.

126.

Pan

Chen

Zhu

Xiang

Peng

Chen

Fang

Guo

, et al. Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study. Oncotarget. 2016;7(11):12089–101.

127.

Poncelet

Nizet

Vercruysse

Hiel

Saliez

Gianello

. Inhibition of humoral response to allogeneic porcine mesenchymal stem cell with 12 days of tacrolimus. Transplantation. 2008;86(11):1586–95.

128.

Buron

Perrin

Malcus

Héquet

Thaunat

Kholopp-Sarda

Moulin

Morelon

. Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneic responses: an in vitro study using human cells. Transplant Proc. 2009;41(8):3347–52.

129.

Maccario

Moretta

Cometa

Montagna

Comoli

Locatelli

Podestà

Frassoni

. Human mesenchymal stem cells and cyclosporin a exert a synergistic suppressive effect on in vitro activation of alloantigen-specific cytotoxic lymphocytes. Biol Blood Marrow Transplant. 2005;11(12):1031–32.

130.

Eggenhofer

Renner

Soeder

Popp

Hoogduijn

Geissler

Schlitt

Dahlke

. Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. Transpl Immunol. 2011;25(2-3):141–47.

131.

Lee

Kim

Lee

Kim

Lee

Chang

Bae

Hong

, et al. Effect of a combination of prednisone or mycophenolate mofetil and mesenchymal stem cells on lupus symptoms in MRL.Fas^lpr mice. Stem Cells Int. 2018;2018:4273107.

132.

Duan

Yang

Huang

Liu

Chen

Ding

. Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells. Biochem Biophys Res Commun. 2018;506(3):619–25.

133.

Ezquer

Bahamonde

Huang

Ezquer

. Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy. Stem Cell Res Ther. 2017;8(1):20.

134.

Lanthier

Lin-Marq

Rubbia-Brandt

Clément

Goossens

Spahr

. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial. Hepatology. 2016;64(6):2185–97.

135.

Wang

Sui

Wang

Huang

Zhang

Chen

Zhang

. Mesenchymal stem cell-seeded regenerated silk fibroin complex matrices for liver regeneration in an animal model of acute liver failure. ACS Appl Mater Interfaces. 2017;9(17):14716–23.

136.

Jang

Kim

Cho

Kim

Park

Cha

Kim

Chang

Baik

. Synergistic effects of simvastatin and bone marrow-derived mesenchymal stem cells on hepatic fibrosis. Biochem Biophys Res Commun. 2018;497(1):264–71.

137.

Zhang

Sun

Zheng

Guo

Zhang

. In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: therapeutic effect on liver fibrosis/cirrhosis. World J Gastroenterol. 2017;23(46):8152–68.

138.

Fiore

Bayo

Garcia

Malvicini

Lloyd

Piccioni

Rizzo

Peixoto

Sola

Atorrasagasti

Alaniz

, et al. Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. Stem Cells Dev. 2015;24(6):791–801.

139.

Jiang

Wang

Qiao

Guo

Wang

Turng

. Polycaprolactone nanofibers containing vascular endothelial growth factor-encapsulated gelatin particles enhance mesenchymal stem cell differentiation and angiogenesis of endothelial cells. Biomacromolecules. 2018;19(9):3747–53.

140.

Kuchroo

Dave

Vijayan

Viswanathan

Ghosh

. Paracrine factors secreted by umbilical cord-derived mesenchymal stem cells induce angiogenesis in vitro by a VEGF-independent pathway. Stem Cells Dev. 2015;24(4):437–50.

141.

Park

Hwang

Jin

Jung

Ryu

Kim

. CCN1 secreted by tonsil-derived mesenchymal stem cells promotes endothelial cell angiogenesis via integrin αv β3 and AMPK. J Cell Physiol. 2015;230(1):140–49.

142.

Boomsma

Geenen

. Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis. PLoS One. 2012;7(4):e35685.

143.

Zagoura

Trohatou

Makridakis

Kollia

Kokla

Mokou

Psaraki

Eliopoulos

Vlahou

Roubelakis

. Functional secretome analysis reveals Annexin-A1 as important paracrine factor derived from fetal mesenchymal stem cells in hepatic regeneration. EBioMedicine. 2019;45:542–52.

144.

Guo

Chen

Zhang

Xiang

. Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis. J Zhejiang Univ Sci B. 2016;17(11):831–41.

145.

Barile

Vassalli

. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63–78.

146.

Lai

Chen

Guo

Wang

Liu

Zhou

Huang

Geng

Luo

Huang

, et al. A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD. J Hematol Oncol. 2018;11(1):135.

147.

Jiang

Tan

Cai

Zhao

Mao

Zhang

Yan

Qian

Yan

. Human umbilical cord MSC-derived exosomes suppress the development of CCl4-induced liver injury through antioxidant effect. Stem Cells Int. 2018;2018:6079642.

148.

Huang

Yin

Lin

Cao

Lin

. Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats. J Neurotrauma. 2017;34(24):3388–96.

149.

Chinnici

Pietrosi

Iannolo

Amico

Cuscino

Pagano

Conaldi

. Mesenchymal stromal cells isolated from human fetal liver release soluble factors with a potential role in liver tissue repair. Differentiation. 2019;105:14–26.

150.

Lou

Song

Yang

Wang

Chen

Liu

. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 2015;8:122.

Research Status of Mesenchymal Stem Cells in Liver Transplantation

Abstract

Keywords

Introduction

Research Status of MSCs

MSC In Vitro Studies

MSC In Vivo Studies

Current Status of Clinical Liver Transplantation

MSCs in Animal Models

MSCs in Clinical Trials

MSCs Combined with Immunosuppressive Drugs in Liver Transplantation

Potential Therapeutic Properties of MSCs in Liver Transplantation

Conclusions

Footnotes

Author Notes

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References