Advance of Mesenchymal Stem Cells in Chronic End-Stage Liver Disease Control

Gao, Yun; Yin, Xiushan; Ren, Xiaomeng

doi:https://doi.org/10.1155/2022/1526217

Stem Cells International

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Abstract Introduction Abbreviations Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 1526217 | https://doi.org/10.1155/2022/1526217

Advance of Mesenchymal Stem Cells in Chronic End-Stage Liver Disease Control

Yun Gao,¹Xiushan Yin,¹and Xiaomeng Ren¹

Academic Editor: Mustapha Najimi

Received12 May 2022

Revised18 Sept 2022

Accepted25 Sept 2022

Published07 Oct 2022

Abstract

The chronic liver diseases will slowly develop into liver fibrosis, cirrhosis, and even liver cancer if no proper control is performed with high efficiency. Up to now, the most effective treatment for end-stage liver diseases is liver transplantation. However, liver transplantation has the problems of donor deficiency, low matching rate, surgical complications, high cost, and immune rejection. These problems indicate that novel therapeutic strategies are urgently required. Mesenchymal stem cells (MSCs) are somatic stem cells with multidirectional differentiation potential and self-renewal ability. MSCs can secrete a large number of cytokines, chemokines, immunomodulatory molecules, and hepatotrophic factors, as well as produce extracellular vesicles. They alleviate liver diseases by differentiating to hepatocyte-like cells, immunomodulation, homing to the injured site, regulating cell ferroptosis, regulating cell autophagy, paracrine effects, and MSC-mitochondrial transfer. In this review, we focus on the main resources of MSCs, underlying therapeutic mechanisms, clinical applications, and efforts made to improve MSC-based cell therapy efficiency.

1. Introduction

Worldwide, approximately 2 million people die each year from liver diseases, accounting for 3.5% of all deaths [1]. Chronic alcohol abuse, virus infection, and autoimmune attacks stimulate hepatocyte apoptosis, endothelial barrier damage, inflammatory cell recruitment, and hepatic stellate cell (HSC) activation [2], resulting in liver fibrosis. Liver fibrosis slowly develops into liver cirrhosis, hepatocellular carcinoma (HCC), and eventually death from liver failure. Up to now, no effective treatment for end-stage liver diseases has been explored, except for liver transplantation. However, high costs, limited donors, and immune rejection after surgery limit the clinical utility of liver transplantation.

MSCs are mesoderm-derived multipotent stem cells with high self-renewal capacity and differentiation potential, which are widely found in a variety of tissues throughout the body. They can differentiate into mesodermal cell lineages and other germ layer lineages, including adipocytes, osteocytes, chondrocytes, and hepatocyte-like cells [3]. MSCs strongly express CD13, CD29, CD105, and CD44, weakly express CD106, do not express CD14, CD34, CD11a, CD31, CD45, and HLA II antigens, and neither express nor weakly express HLA I antigen [4]. MSCs have been demonstrated to be an effective therapeutic strategy in end-stage liver diseases due to their ability to transdifferentiate into the hepatocyte-like cells, immunomodulatory potential, paracrine activity, antioxidative capacity, derived extracellular vesicles, and regulation of cell ferroptosis and autophagy. This review will primarily focus on MSC resources, underlying therapeutic mechanisms, a summary of clinical applications, and several efforts made to improve MSC performance in treating end-stage liver diseases.

2. Main Resources of MSCs

MSCs are nonhematopoietic stem cells derived from the human mesoderm and widely distributed in the bone marrow, umbilical cord, adipose, and other tissues. MSCs were initially identified and isolated from bone marrow as adherent cells. But due to their limited numbers (0.01-0.001% of total bone marrow cells) [5] and the invasive isolation from bone marrow, researchers have explored other possible sources of MSCs. Several studies have reported the successful isolation of MSCs from various tissues with similar in vitro properties, including adipose tissue [6], umbilical cord [7], umbilical cord blood [8], synovium [9], amniotic fluid [10], and placenta [11], as shown in Figure 1. MSCs strongly express CD13, CD29, CD105, and CD44, weakly express CD106, do not express CD14, CD34, CD11a, CD31, CD45, and HLA II antigens, and neither express nor weakly express HLA I antigen [4]. The immunophenotypes of MSCs make it possible to be transplanted in an autologous or an allogeneic way, which broadens clinical applications. However, there are differences in the surface markers of MSCs due to the MSC sources [12], donor age [13], isolation methods [14], and culture conditions [15]. In vitro, MSCs of different origins differ in their ability to expand. Kern et al. found that bone marrow-derived MSCs (BMMSCs) had the lowest proliferation capacity and the shortest culture period, while umbilical cord-derived MSCs (UCMSCs) possessed the highest proliferation capacity and the longest culture period [16]. Similarly, MSCs from different sources exhibited different trilineage differentiation. Heo et al. found that UCMSCs can differentiate into adipose, bone, and cartilage and have a faster rate of osteogenesis with more ALP-positive cells and bone node formation under the same osteogenic conditions. UCMSCs and BMMSCs were both capable of differentiating into chondrocytes [17]. Besides, there were some differences in paracrine factor levels and immunomodulatory potential [18, 19].

2.1. Bone Marrow

In 1976, Friedenstein et al. found fibroblast precursors in the bone marrow, spleen, and thymus of adult mice, which could proliferate in vitro adherently, differentiate into other cell types, and showed colony growth capacity [20]. Subsequently, Pittenger et al. and Prockop found that fibroblast precursors contained MSCs, which could differentiate into multiple mesenchymal tissues, including bone, cartilage, adipose, and smooth muscle [3, 21]. Due to their linkage with the formation of mesenchymal tissues during embryonic development, these cells were termed “MSCs” [22]. Constrained by the limited number of BMMSCs and the invasive nature of harvesting, researchers have explored other possible sources of MSCs, like the umbilical cord [23], adipose tissue [24], and umbilical cord blood [17].

2.2. Umbilical Cord

In 1991, McElreavey et al. firstly isolated and characterized fibroblast-like cells from the Wharton’s jelly portion of the human umbilical cord [7], which were found to differentiate into cartilage tissue when treated with TGF-β [25]. In 2005, Sarugaser et al. firstly isolated the nonhematopoietic human umbilical cord perivascular (UCPV) cell population. Human UCPV cells could expand rapidly and did not express MHC molecules, indicating that they could be applied for allogeneic mesenchymal cell-based therapies [26]. MSCs can be isolated from several compartments within the umbilical cord, including the umbilical vein, umbilical artery, and perivascular tissue of the umbilical cord, Wharton’s jelly, and subamniotic tissue. Furthermore, UCMSCs are more primitive and abundant than MSCs isolated from other tissues. They are less likely to be contaminated by pathogenic sources and have a higher proliferation capacity than BMMSCs. UCMSCs have lower immunogenicity, no ethical controversy, and no harm to infants or mothers [17, 27].

2.3. Adipose

In 2002, Zuk et al. isolated MSCs from adipose tissue for the first time [28]. Adipose tissue is another source of MSCs. Obtaining adipose tissue is easier and less invasive than bone marrow, allowing it to be widely used [29]. Adipose-derived MSCs (ADMSCs) have multilineage differentiation potential and self-renewal capacity. The expression of stemness markers for different sources of MSCs showed the differences. BMMSCs highly expressed SOX2, MYC, KLF4, NANOG, and INHBA and did not express OCT4, LIN28, and REX1. ADMSCs highly expressed MYC, KFL4, NANOG, LIN28, REX1, and INHBA and did not express OCT4 and SOX2. There were no significant differences between BMMSCs and ADMSCs in growth rate, colony-forming efficiency, and immunophenotype. BMMSCs and ADMSCs had the same trilineage differentiation capacity and gene expression profiles [17].

2.4. Pluripotent Stem Cell

In 2010, Lian et al. derived multipotent MSCs from human-induced pluripotent stem cells (iPSC-MSCs) [30]. iPSC-MSCs have been developed with a higher proliferation rate without loss of their key characteristics and engraftment capacity than other sources of MSCs [31, 32]. Furthermore, iPSC-MSCs had similar efficiencies with BMMSCs in homing to cancers but were much less prone than BMMSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and proliferation of cancer cells [33]. Therefore, the in vitro differentiation of iPSC into MSCs may be proposed as a novel alternative resource, which helps to overcome several limitations of adult MSCs as seen in BMMSCs. Induction of glutathione peroxidase 3 (GPx3), which is reduced in senescence, from iPSC-MSCs can effectively control ischemia-reperfusion-induced liver injury via alleviating hepatic senescence [34] The limitations of adult MSCs sometimes were discussed as follows: iPSC-MSCs show a better competence in expansion, preserving differentiation capacity and proper karyotypes for 120 doublings, while BMMSCs become senescent after 20 doublings [30]. Besides, when isolated from elderly subjects or patients with age-related disorders, BMMSCs may exhibit reduced survival and differentiation ability, and iPSC-MSCs may overcome the aging-associated impairment of BMMSCs. This might be significant given that age is a factor in the prevalence, morbidity, and mortality of some diseases [35]. iPSC-MSCs also secreted abundant factors which can suppress inflammatory-like stem cell factor (SCF) [35], monocyte chemotactic protein 1 (MCP) [36], TGF-β1/2/3 [33], and FGF21 [37]. The consistency, quality control, and sufficient quantity have always been challenges of MSCs in clinical trials and medication development. iPSC-MSCs turned out to be effective solutions to solve these problems [38].

3. Underlying Mechanism of MSCs in Treating End-Stage Liver Diseases

MSCs have several potential regulatory mechanisms for the treatment of liver disease, including paracrine secretion, immune regulation, hepatocyte-like cell differentiation, antioxidation, regulation of cell ferroptosis, regulation of cell autophagy, and MSC-mitochondrial transfer, as shown in Figure 1.

3.1. Paracrine

MSCs have been shown to induce liver repair, ameliorate systemic inflammation, promote angiogenesis, and inhibit cell death and fibrosis through paracrine effects. Paracrine action is based on the secretion of cytokines, chemokines, trophic factors, and extracellular vesicles (EVs) [39–41]. This part focuses on MSC-derived EVs and nutritional molecules.

MSC-derived EVs contain exosomes (Exs). Exs are membrane-derived nanoscale vesicles that carry large amounts of proteins, nucleic acids, lipids, and metabolites that can be released and taken up by most cells [42]. MSC-derived Exs (MSC-Exs) have received a lot of attention as the most important potential cell-free therapeutic approach for liver diseases [43]. Exs derived from human UCMSCs (HUCMSC-Exs) reduced collagen deposition and oxidative stress in the liver, inhibited intrahepatic inflammatory cell infiltration, hepatocyte apoptosis, and liver structural damage, and improved CCl4-induced mouse liver fibrosis [44]. Moreover, HUCMSC-Exs significantly improved liver function, inactivated the TGF-β1/Smad signaling pathway, and inhibited EMT, which is a physiological process during liver fibrosis [45]. Human BMMSC-derived Exs (HBMMSC-Exs) repaired the liver structure and decreased fibrous capsules, collagen fibers, and lipid peroxidation changes in the rat liver intoxicated with CCl4. Besides, HBMMSC-Exs alleviated liver inflammation, improved liver function, and promoted liver regeneration. Mechanically, those Exs suppressed HSC activation through the Wnt/β-catenin signaling pathway [46].

MSCs can also secrete a large number of liver nutritional factors, which are constituents of the MSC secretome, to promote hepatocyte proliferation, reprogram HSCs, and enhance angiogenesis, such as hepatocyte growth factor (HGF) [47], nerve growth factor (NGF) [48], epidermal growth factor (EGF) [49], transforming growth factor (TGF) [47], and insulin-like growth factor-1 (IGF-1) [50]. HSCs play an important role in liver fibrosis pathogenesis. Thus, blocking HSC proliferation and enhancing HSC apoptosis can be a promising treatment for liver fibrosis. MSCs secreted HGF and TGF-3, which increased p21 and p27 while decreasing cyclinD1, leading to HSCs G (0)/G (1) arrest eventually [47]. MSC-derived HGF induced activated HSC apoptosis. Neutralizing HGF exhibited a weakened proapoptotic effect [51]. Besides, MSCs produced NGF, which promoted HSC apoptosis via NF-κB and B cell leukemia-xl (Bcl-xl) molecules [48]. Milk fat globule-EGF factor 8 (MFGE8), one of the soluble proteins from the UCMSC secretome, significantly downregulated HSC activation by reducing the TGF-β1 receptor of HSCs [49]. Three-dimensional- (3D-) cultured ADMSCs, which produced high levels of HGF, IGF-1, SDF-1, and other proteins, showed a protective effect on liver fibrosis [50].

3.2. Immunomodulation

As an immune organ, the liver has a variety of immune cells, including infiltrating monocyte-derived macrophages, Kupffer cells, neutrophils, dendritic cells (DCs), natural killer (NK) cells, T cells, and B cells. Multiple immune cells secrete cytokines, chemokines, and other inflammatory factors to maintain liver homeostasis [52]. MSCs act as regulators for a variety of immune cells [53]. For end-stage liver diseases in animal models and clinical trials, MSCs secrete various immunosuppressive soluble mediators to inhibit T cell proliferation and activation, including IL-10 [27, 54] and indoleamine 2,3-dioxygenase (IDO) [55]. MSCs or MSC-conditioned medium (MSC-CM) treatment increased IL-10 and IDO levels in serum and ameliorated CCl4-induced liver fibrosis through downregulating IL-17 producing CD4+ T cells and upregulating IL-10 producing CD4+ T cells in the liver. Moreover, IDO inhibitor decreased the capacity of MSC-CM. Thus, IDO secreted by MSCs regulated liver fibrosis [55]. In steatohepatitis-induced liver fibrosis, ADMSCs restored liver function, improved parenchymal cell regeneration, and ameliorated liver fibrosis. ADMSCs decreased the ratio of CD8+/CD4+ T cells, which was consistent with the downregulation of antigen presentation and helper T-cell activation genes [56]. Primary biliary cirrhosis (PBC) is one of the most common types of liver cirrhosis. BMMSC transplantation significantly increased CD4+ Foxp3+ regulatory T cell levels in peripheral blood and in lymph nodes. Besides, BMMSCs reduced IFN-γ and elevated TGF-β1 in serum without affecting IL-10 expression [54]. From clinical trials, we can better understand the immunomodulatory role of MSCs. In a clinical trial for chronic hepatitis B-induced decompensated liver cirrhosis, human UCMSC administration reduced TNF-α and IL-6 levels markedly in serum compared to the control group [27]. Besides, human UCMSCs accelerated IL-10 production. CD4+ T cells and regulatory T cells were higher in the human UCMSC treatment group, while CD8+ T cells and B cells were much lower than in the control group [27]. For UDCA-resistant PBC, BMMSC transplantation improved liver function. In peripheral lymphocytic subsets, CD8+ T cells decreased, while CD4+ CD25+ Foxp3+ T cells increased. Besides, IL-10 levels in serum elevated [57]. BMMSC administration for HBV-related liver cirrhosis markedly improved regulatory T cells and reduced Th17 cells compared to the control group. Serum TGF-β levels were elevated, while IL-17, IL-6, and TNF-α were lower in the transplantation group than in the control [58]. All the data showed that MSC treatment exhibited immunomodulatory effects in the regulation of liver cirrhosis.

3.3. Hepatocyte-Like Cell Differentiation

Hepatocytes undergo apoptosis [59], necrosis [60], and pyroptosis [61] in the liver fibrosis/cirrhosis, resulting in the loss of normal hepatocytes and the damage of parenchymal structure and function. MSCs have the potential to differentiate into hepatocyte-like cells, making it possible to reconstruct the parenchyma of the liver [62]. Numerous approaches can promote MSCs transdifferentiating into hepatocyte-like cells [62]. Supplementation with growth factors, cytokines [63–65], and other compounds, like Chinese medicine [66, 67], promoted the conversion of MSCs to hepatocyte-like cells, alleviating liver fibrosis and cirrhosis. Genetic modification enhanced the differentiation of MSCs to hepatocyte-like cells and promoted liver function recovery in animal liver cirrhosis models [68]. In addition, changing the culture microenvironment of MSCs affected the differentiation capacity. MSCs expressed liver-specific genes, like albumin, CK-18, CK-19, and AFP when cocultured with liver cells [69]. 3D culture maintains adult hepatocyte function and the maturation of hepatic progenitors [70]. MSCs cultured in cell pellets and cell pellets supplemented with extracellular matrix (ECM) induced hepatic differentiation of MSCs [71]. In the preclinical experiments, MSC transplantation to the fibrotic or cirrhotic liver stimulated the production of hepatocyte-like cells and facilitated the repair of liver function [72, 73].

3.4. Antioxidative Capacity

Excessive ROS production exceeds the scavenging capacity of antioxidants in end-stage liver diseases, causing oxidative stress and hastening the pathogenesis of liver fibrosis or cirrhosis [60]. Clearing large amounts of ROS and improving antioxidant performance can be a promising strategy for end-stage liver disease treatment. BMMSCs showed antioxidative activity in end-stage liver diseases. BMMSCs migrated into injured sites in liver fibrosis animal models [74, 75], significantly reduced ROS production [76], downregulated lipid peroxidation (LPO) [75], improved SOD activity [76, 77], and increased GSH [74, 75] and antioxidant enzyme levels via Nrf2/HO-1 signaling pathway [75, 78]. In addition to BMMSCs, human amniotic membrane-derived MSCs significantly reduced oxidative stress in decompensated liver cirrhosis [79].

3.5. MSCs Regulate Cell Ferroptosis

Ferroptosis is one kind of programmed cell death different from apoptosis, necrosis, and autophagy, which is iron-dependent [80] and related to the pathogenesis of many diseases, like Parkinson’s syndrome [81], cancers [82], and liver diseases [83]. Human UCMSC-Exs induced human hepatic stellate cell line ferroptosis in vitro without affecting hepatocyte ferroptosis. Mechanically, human UCMSC-Exs-derived BECN1 induced LX2 ferroptosis by reducing system xc-/GPX4 activity. In contrast, the knockdown of BECN1 weakened the effect of human UCMSC-Exs on LX2 ferroptosis [84]. The data demonstrate that MSCs ameliorate end-stage liver diseases via modulating liver cell ferroptosis.

3.6. MSCs Regulate Cell Autophagy

The delivery of cytoplasmic cargo to the lysosome for degradation is the original scientific definition of autophagy. There are three forms of autophagy up to now, which are chaperone-mediated autophagy, microautophagy, and macroautophagy [85]. Autophagy plays an important role in the preservation of cellular and organism homeostasis [86]. ADMSCs delivered miRNAs to HSCs. ADMSCs overexpressed miR-181-5p communicated with HST-T6 cells mediated by Exs. Exs of miR-181-5p induced HST-T6 cell autophagy via downregulating the STAT3/Bcl-2/Beclin 1 signaling pathway in vitro. Furthermore, ADMSC-Exs of miR-181-5p attenuated liver fibrosis in vitro and in CCl4-induced liver fibrosis of mice [87]. In CCl4-induced liver fibrosis, circRNA (mmu_circ_0000623) was reduced compared to wild-type mice. Interestingly, ADMSC-Exs overexpressed mmu_circ_0000623 markedly inhibited CCl4-induced liver fibrosis by activating miR-125/ATG4D-mediated autophagy. However, the autophagy inhibitor reversed the autophagy activation effects resulting from Exs [88]. Some other sources of MSCs, like tonsil-derived MSCs (TMSCs), ameliorated liver fibrosis in mice by mediating autophagy. After TMSC treatment, autophagy-related proteins were detectable in parenchymal cells, and TGF-β, which is a marker of liver fibrosis, was not observed. Autophagy inhibitor, bafilomycin A1, suppressed the therapeutic effects of TMSCs [89]. All these findings indicate that MSC-mediated autophagy in the liver is a possible mechanism for MSC treatment of liver fibrosis.

3.7. MSC-Mitochondrial Transfer

Mitochondria of mesenchymal stem cells are involved in immune regulation [90–94]. Nonalcoholic fatty liver disease (NAFLD) will further develop into nonalcoholic steatohepatitis (NASH) [95]. NASH is pathologically defined by steatosis, inflammation, hepatocellular damage, and varying degrees of liver fibrosis [96, 97]. BMMSCs transfer alleviated (NASH) induced central carbon, amino acid, and lipid metabolism impairment related to mitochondrial and peroxisomal functional disorders. MSCs reduced fat load in hepatocytes by transferring mitochondria into hepatocytes via tunneling nanotubes (TNTs) [90]. Regulatory T cells (Tregs) have crucial functions in the maintenance of peripheral tolerance, the prevention of autoimmune illnesses, and the limitation of chronic inflammatory diseases [98]. Tregs inhibited inflammation in end-stage liver diseases. Hepatic Tregs downregulated severity of liver fibrosis in CCl4-induced chronic liver inflammation. Depletion of Tregs aggravated inflammation and fibrosis [99]. Direct and indirect contact with allogeneic ADMSCs improved therapeutic potential of Tregs via enhancing immunosuppressive adenosine accumulation and inhibiting the proliferation of conventional T cells. Especially, direct communication between ADMSCs and Tregs was achieved by transferring mitochondria and fragments of plasma membrane to Tregs via direct ADMSCs-Tregs contact in an HLA-dependent way [92]. Mitochondrial transfer from MSCs to human CD3+ T cells increased T cell activation and Treg differentiation-related mRNA expression compared to CD3+ T cells without mitochondria from MSCs, including FoxP3, CTLA4, and GITR. Functional analyses also revealed that transfer of mitochondria induced Treg cell differentiation and increased immunosuppressive efficiency [94]. Although there are few studies on the effect of mitochondrial transfer from MSCs on the activation of regulatory T cells in the treatment of liver fibrosis, this is a promising therapeutic strategy.

iPSC-MSCs as an essential source of MSCs showed impressive therapeutic effects on inflammatory diseases [91, 100–108]. Chronic obstructive pulmonary disease (COPD) exhibits severe fibrosis with mitochondrial dysfunction [93]. Human iPSC-MSCs or adult BMMSC transplantation showed protective effects against cigarette smoke- (CS-) induced lung damage via alleviating linear intercept and severity of fibrosis. MSCs transferred mitochondria to rat airway epithelial cells in lung sections exposed to CS. Furthermore, mitochondrial transfer from iPSC-MSCs to bronchial epithelial cells performed better than BMMSCs, with adenosine triphosphate content preserved. This unique mitochondrial translocation was facilitated by tunneling nanotube (TNT) production. Mitochondrial transfer was stopped when the formation of TNTs was blocked [93]. Similarly, higher expression of intrinsic Rho GTPase 1 (MIRO1) in human iPSC-MSCs than in BMMSCs was responsible for the greater efficiency of mitochondrial translocation in alleviating anthracycline-induced cardiomyocyte (CM) damage. TNF-α/NF-κB/TNFαIP2 signaling pathway was responsible for TNT formation for mitochondrial transfer to CMs [91]. Mitochondrial transfer from iPSC-MSCs to epithelial cells in asthma rescued mitochondrial dysfunction in epithelial cells and downregulated asthma inflammation in vivo via TNT formation between iPSC-MSCs and epithelial cells [101]. Mitochondrial dysfunction was also observed in hypoxia-ischemia-induced brain injury. In vitro, TNTs were formed between iPSC-MSCs and PC12, a kind of neural cell lines. PC12 damage was relieved by transfer of mitochondria via TNTs. Damage to the channel reduced the effectiveness of the protection [108]. These data showed prospects for cell-based therapies for end-stage liver disease.

4. Clinical Application of MSCs in the Treatment of Chronic End-Stage Liver Diseases

In recent years, MSCs have brought a new dawn to treating various significant diseases, and related clinical research has been carried out in many countries. To date, approximately 11529 MSCs studies are documented on clinicaltrials.gov (https://clinicaltrials.gov). They mainly treat graft-versus-host disease (GVHD), hematopoietic system diseases, liver fibrosis/cirrhosis, diabetes, autoimmune diseases, and neurodegenerative diseases. 4019 studies have been completed, and most clinical phase II trials have yielded positive results, demonstrating that MSC-based therapy has broad application potential [23, 109, 110]. The liver is a vital organ with detoxification and regenerative capacities. However, viruses, alcohol, and other factors chronically damage hepatocytes and the endothelial barrier, inducing inflammatory cell infiltration, leading to massive production of collagen and extracellular matrix accumulation by activated HSCs, resulting in liver fibrosis, which will progress to cirrhosis in advanced stages. Liver failure occurs when the damage exceeds the compensatory capacity of the liver. Currently, the most effective treatment for liver failure is orthotopic liver transplantation. However, due to the shortage of donor organs, high costs, and the need for lifelong immunosuppressive drugs, liver transplantation cannot be used widely. According to https://clinicaltrials.gov, traditional treatments for chronic end-stage liver diseases include dietary supplementation, chemotherapy, and surgery. Due to the shortcomings of traditional treatment methods, MSC-based therapy gains attention as a potential therapeutic approach, as shown in Figure 2. There are 14 clinical trials in PubMed searching for “liver cirrhosis” and “mesenchymal stem cell”, which are listed in Table 1. Focusing on ongoing or completed clinical trials of MSCs in liver fibrosis/cirrhosis, which are registered at https://clinicaltrials.gov, approximately 68 studies demonstrated the popularity of MSCs. We listed the top 29 most recent studies with the highest correlation, as shown in Table 2.

5. Efforts to Improve the Therapeutic Performance of MSCs

5.1. Gene-Modified MSCs

Modification of MSCs using genetic engineering technologies can improve therapeutic outcomes for liver diseases [123]. Viral vector-mediated gene modification provides a potential new approach for remodeling MSCs, including lentiviruses, adenoviruses, and retroviruses, which enables MSCs to express a variety of exogenous genes with high expression and hardly affects the biological characteristics of MSCs [124]. Genes transfected into MSCs are classified as MMPs [125], microRNAs [87, 126], trophical factors [63, 127–130], transcription factors [131, 132], and ECM protein [133].

Matrix metalloproteinases (MMPs) take charge of degrading ECM [134]. MMP-1 was transduced into BMMSCs by a recombinant adenovirus vector. BMMSCs which overexpressed MMP-1 alleviated CCl4-induced liver fibrosis and liver injury [125]. MSC-Exs contain numerous microRNAs, which regulate intracellular signaling pathways [135]. In vitro assays revealed that ADMSCs overexpressing miR-181-5p built cell communication with HST-T6. miR-181-5p inhibited HST-T6 activation and promoted HST-T6 autophagy via direct targeting of Bcl-2 and STAT3. Moreover, ADMSCs-Exs containing miR-181-5p alleviated CCl4-induced liver fibrosis in vitro and in vivo [87]. Similarly, miR-122-modified ADMSCs by lentivirus significantly blocked HSC proliferation and collagen maturation. Exs produced by MSCs released miR-122 and facilitated communication between ADMSCs and HSCs. miR-122-modified ADMSCs showed better therapeutic effects against CCl4-induced liver fibrosis [126]. Erythropoietin (EPO), a glycoprotein hormone, is mainly produced by the kidney and can be found in other tissues, exhibiting anti-inflammation [136], neuroprotective [137], antioxidative stress [138], and antiapoptosis functions [139]. EPO modification enhanced BMMSC viability and migration ability. EPO-modified BMMSCs increased therapeutic efficacy towards liver fibrosis in an animal model. Besides, EPO elevated cytokines released from BMMSCs against liver injury [127]. HGF plays an important role in hepatocyte regeneration [140]. Besides, HGF can inhibit tissue fibrosis and apoptosis [141–143]. HGF modification improved the migration capacity of ADMSCs to injury sites. In addition, HGF-modified ADMSCs alleviated radiation-induced liver fibrosis and promoted liver regeneration as well as liver function [128]. Human UCMSCs modified with HGF improved liver function and recovered body weight and liver weight, thereby attenuating CCl4-induced liver fibrosis in rats [129]. IGF-1 is an essential hormone in metabolism, which is mainly produced by the liver. IGF-1 was downregulated in liver cirrhosis [144]. Modifying BMMSCs with the IGF-1 gene did not affect the immunogenicity of MSCs. Furthermore, IGF-1-modified BMMSCs mitigated liver fibrosis in mice through downregulation of HSC activation. IGF-1-modified BMMSCs-CM elevated HGF transcriptional levels in hepatocytes [130]. Fibroblast growth factors (FGFs) regulate cell proliferation, differentiation, and migration [145]. Among FGF family members, FGF4 possesses the highest mitogenic activity in vitro [146–148]. FGF4-modified BMMSCs showed enhanced stemness. Moreover, FGF4 promoted BMMSC migration to the cirrhotic sites of the liver, leading to the improvement of hepatocyte and hepatic progenitor cell (HPC) proliferation [63]. Smad7 is a negative regulator of the TGF-β1/Smad signaling pathway, which is required for the pathogenesis of liver fibrosis [149]. BMMSCs transduced with the Smad7 gene via a lentivirus vector exerted therapeutic effects by reducing fibrosis biomarkers, such as collagen I and III, TGF-β1, αSMA, TGF-β1R, and TIMP-1 [131]. Hepatocyte nuclear factor-4α (HNF-4α), as a transcription factor, regulates mature liver cell marker expression and plays a key role in liver cell maturation [150, 151]. Overexpressing HGF-4α in BMMSCs ameliorated CCl4-induced hepatocyte necrosis and fibrosis, and enhanced liver injury repair without affecting the homing of MSCs. Besides, HGF-4α-modified BMMSCs downregulated Kupffer cell activation and promoted iNOS expression via the NF-κB signaling pathway, thus reducing liver inflammation [132]. ECM1, which is secreted by hepatocytes, regulates hepatic homeostasis. ECM1 is identified as a differentially expressed gene in liver cirrhosis, which is downregulated under cirrhotic conditions [133]. ECM1 expression was reduced during fibrotic pathogenesis in the liver, while ECM1 supplementation prevented fibrosis [152]. Hair follicle-derived MSCs (HFMSCs) were genetically modified with lentivirus to overexpress ECM1. ECM1-modified HFMSCs blocked the activation of HSCs via inhibiting the TGF-β/Smad signaling pathway in vitro and in vivo. Besides, ECM1-modified HFMSCs migrated to the injury sites of the liver and expressed hepatocyte-specific surface markers, thus ameliorating liver fibrosis and promoting liver repair and enhancing liver function [133]. All data suggest that genetic modification of MSCs is beneficial in enhancing therapeutic effects for liver fibrosis.

5.2. Pretreatment of MSCs

Due to the severe oxidative stress microenvironment in end-stage liver diseases, preincubation of MSCs with antioxidants improves the effectiveness of MSCs [153]. Melatonin (MT) is an endogenous neurohormone produced mainly by the pineal gland that exerts immunomodulatory, anti-inflammatory, cytoprotective, and antioxidant effects [154]. Similar to BMMSCs without preincubation, MT-pretreated BMMSCs (MT-BMMSCs) showed protective effects against liver fibrosis. MT-BMMSCs, on the other hand, migrated to injury sites in the liver more than nontreated BMMSCs [155]. Another study showed that MT-BMMSCs performed better than nontreated MSCs, especially in elevating glycogen storage, downregulating liver fibrosis, and reversing liver function [156]. Vitamin E pretreatment of Wharton’s jelly-derived MSCs (Vit E-WJMSCs) ameliorated CCl4-induced hepatocyte injury in vitro. Furthermore, Vit E-WJMSCs recovered CCl4-induced liver fibrosis in rats and increased homing of WJMSCs [153]. In vitro, GSH or MT preconditioning improved ADMSC survival and migration. GSH or MT pretreatment of ADMSCs (GSH-ADMSCs or MT-ADMSCs) enhanced cell engraftment in the injury sites in vivo and restored live function in liver fibrosis [157]. Icariin (ICA), a traditional Chinese medicine, promoted the migration of UCMSCs towards the damaged liver tissue. Furthermore, ICA-treated UCMSCs accelerated liver function recovery from CCl4 intoxication, reduced oxidative stress, and blocked the progression of liver fibrosis in mice [158]. Enhancement of MSC-converted hepatocyte-like cells is a strategy to improve the therapeutic effect. MSCs pretreated with injured liver tissue increased the expression levels of hepatocyte markers compared to normal liver tissue preconditioning. Additionally, pretreatment of MSCs with injured liver tissue increased their glycogen storage capacity. Transplantation of pretreated MSCs improved their localization and differentiation ability in liver fibrosis mouse models, reducing liver fibrosis and improving liver function. After engraftment, pretreated MSCs showed elevated marker expression for hepatocyte differentiation [159].

5.3. MSC Spheroids

The traditional two-dimensional (2D) culture of MSCs exhibits several shortcomings in treating liver diseases, including large-scale expansion of cells, poor survival in vivo, and the loss of original properties [160]. Spheroid culture is a novel 3D culture method that preserves natural characteristics such as stemness and secretion, facilitates cell-to-cell and cell-to-matrix communication, creates an in vivo-like growth microenvironment, and improves survival and proliferation [161]. Numerous attempts at preparing 3D-cultured MSCs show advantages in treating end-stage liver disease. Collagen fiber-based 3D spheroids of ADMSCs preserved cell function and paracrine secretion capacity. In addition, transplantation of 3D ADMSCs spheroids alleviated TAA-induced liver cirrhosis in mice [70]. Human-exfoliated deciduous teeth (EDT) are another promising source of MSCs. Hepatocyte-like cells derived from human EDT-MSCs formed spheroids without a scaffold and were transplanted into the livers of mice with CCl4-induced liver fibrosis, where they engrafted, improved liver function, and demonstrated antifibrosis efficacy in mice [162]. Conditioned medium derived from 3D spheroid-derived ADMSCs protected hepatocytes from CCl4-induced injury in vitro by inhibiting hepatocyte apoptosis and LDH release. Furthermore, 3D spheroid-derived ADMSCs improved liver function and reduced liver fibrosis in mice with hepatic fibrosis [163].

5.4. Current Challenges and Future Perspectives

The role of MSCs in end-stage liver disease control has been studied in recent years, and substantial progress has been made in understanding how MSCs improve liver diseases. Besides, numerous attempts have been made to enhance the therapeutic effects of MSCs. However, several challenges remain to improving the efficacy of MSCs in the treatment of liver diseases and increasing clinical application.

The consistency, quality control, and sufficient quantity have always been challenges for MSCs in clinical trials and medication development. MSCs come from various origins with unique biological characteristics. Consequently, it is difficult to standardize MSC production and MSC medication [164]. For the treatment of end-stage liver disease, different sources of MSCs should be compared in immunomodulatory, antifibrotic, and liver regenerative capacity to create the optimal treatment strategy. iPSC-MSCs can resolve the issues of inconsistent quality, challenging preparation, and insufficient quantity [38].

The MSC-mitochondrial transfer is one of the benefits of MSCs in treating liver diseases. However, the detailed mechanisms involved have not been sufficiently investigated. Mitochondrial dynamics take part in regulating MSC functions. Some key molecules, including mitofusin 1 and mitofusin 2 (MFN 1 and MFN 2, respectively) [165], optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1) regulate MSC dynamics. Posttranslational modifications have also been reported in regulating mitochondria dynamics [166, 167]. The knockout of the key molecules downregulated mitochondria dynamics of MSCs [168]. Certain bioactive compounds enhanced the mitochondrial dynamics and functions of MSCs and increased the efficiency of MSCs [169]. Additionally, 2D and 3D MSC cultures influenced mitochondria dynamics and immunomodulatory functions of MSCs [170]. It is necessary to clarify whether increasing mitochondrial dynamics enhance MSCs in the treatment of end-stage liver disease.

Although MSCs have been widely tested in preclinical and clinical studies of end-stage liver disorders such as liver fibrosis and cirrhosis, there are various issues that must be addressed to improve MSC-based therapy. The pathogenesis of liver fibrosis is a complicated process, and the immunological milieu differs at various phases of pathogenesis. The course of liver fibrosis and the timing of MSC injections must be evaluated.

In a clinical trial, only after patients were infused with UCMSCs for 13 months did survival rates increase [111]. However, further research is needed to determine the precise mechanism by which UCMSC treatment improves survival only after 13 months of treatment.

The ineffectiveness of MSC homing to the injury site is a problem we are facing. Several attempts have been made to enhance MSC homing ability, such as overexpressing CXCR4 or CXCR7 in MSC, which are sensitive to SDF-1. Though the establishment of the chemokine/chemokine receptor axis can help solve this problem in animal models, its safety and efficacy are needed to be investigated in clinical trials [171, 172].

Abbreviations

MSCs:	Mesenchymal stem cells
HSCs:	Hepatic stellate cells
HCC:	Hepatocellular carcinoma
PSC:	Pluripotent stem cell
BMMSCs:	Bone marrow-derived MSCs
UCMSCs:	Umbilical cord-derived MSCs
UCPV:	Umbilical cord perivascular
ADMSCs:	Adipose-derived MSCs
iPSC-MSCs:	Induced pluripotent stem cell-derived MSCs
EVs:	Extracellular vesicles
Exs:	Exosomes
MSC-Exs:	MSC-derived Exs
HUCMSC-Exs:	Exs derived from human UCMSCs
BMMSC-Exs:	BMMSC-derived Exs
HGF:	Hepatocyte growth factor
NGF:	Nerve growth factor
EGF:	Epidermal growth factor
TGF:	Transforming growth factor
IGF-1:	Insulin-like growth factor-1
Bcl-xl:	B cell leukemia-xl
MFGE8:	Milk fat globule-EGF factor 8
3D:	Three-dimensional
DCs:	Dendritic cells
NK cells:	Natural killer (NK) cells
IDO:	Indoleamine 2,3-dioxygenase
MSC-CM:	MSC-conditioned medium
PBC:	Primary biliary cirrhosis (PBC)
ECM:	Extracellular matrix
LPO:	Lipid peroxidation
TMSCs:	Tonsil-derived MSCs
GVHD:	Graft-versus-host disease
MMPs:	Matrix metalloproteinases
EPO:	Erythropoietin
FGFs:	Fibroblast growth factors
HPCs:	Hepatic progenitor cells
HNF-4α:	Hepatocyte nuclear factor-4α
HFMSCs:	Hair follicle-derived MSCs
MT:	Melatonin
MT-BMMSCs:	MT-pretreated BMMSCs
Vit E-WJMSCs:	Vitamin E pretreatment of Wharton’s jelly-derived MSCs
GSH-ADMSCs/MT-ADMSCs:	GSH or MT pretreatment of ADMSCs
ICA:	Icariin
2D:	Two-dimensional
EDT:	Exfoliated deciduous teeth
EDT-MSCs:	Exfoliated deciduous teeth-derived MSCs.

Data Availability

All the data is available at https://clinicaltrials.gov and PubMed database.

Conflicts of Interest

The authors have no conflict of interest to declare.

Authors’ Contributions

Yun Gao drafted the work. Xiushan Yin conceived and revised the work. Xiaomeng Ren conceived, revised, and edited the work. All authors have read and approved the final manuscript.

Acknowledgments

This work was supported by program from the Department of Education of Liaoning Province (LQ2020022 and LJKZ0444).

References

S. K. Asrani, H. Devarbhavi, J. Eaton, and P. S. Kamath, “Burden of liver diseases in the world,” Journal of hepatology, vol. 70, no. 1, pp. 151–171, 2019.
View at: Publisher Site | Google Scholar
H. Malhi and G. J. Gores, “Cellular and molecular mechanisms of liver injury,” Gastroenterology, vol. 134, no. 6, pp. 1641–1654, 2008.
View at: Publisher Site | Google Scholar
M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999.
View at: Publisher Site | Google Scholar
D. Mushahary, A. Spittler, C. Kasper, V. Weber, and V. Charwat, “Isolation, cultivation, and characterization of human mesenchymal stem cells,” Cytometry A, vol. 93, no. 1, pp. 19–31, 2018.
View at: Publisher Site | Google Scholar
S. Gronthos, A. C. Zannettino, S. J. Hay et al., “Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow,” Journal of cell science, vol. 116, no. 9, pp. 1827–1835, 2003.
View at: Publisher Site | Google Scholar
P. A. Zuk, M. Zhu, H. Mizuno et al., “Multilineage cells from human adipose tissue: implications for cell-based therapies,” Tissue Eng, vol. 7, no. 2, pp. 211–228, 2001.
View at: Publisher Site | Google Scholar
K. D. McElreavey, A. I. Irvine, K. T. Ennis, and W. H. McLean, “Isolation, culture and characterisation of fibroblast-like cells derived from the Wharton's jelly portion of human umbilical cord,” Biochemical Society Transactions, vol. 19, no. 1, p. 29s, 1991.
View at: Publisher Site | Google Scholar
O. K. Lee, T. K. Kuo, W. M. Chen, K. D. Lee, S. L. Hsieh, and T. H. Chen, “Isolation of multipotent mesenchymal stem cells from umbilical cord blood,” Blood, vol. 103, no. 5, pp. 1669–1675, 2004.
View at: Publisher Site | Google Scholar
C. De Bari, F. Dell'Accio, P. Tylzanowski, and F. P. Luyten, “Multipotent mesenchymal stem cells from adult human synovial membrane,” Arthritis & Rheumatism, vol. 44, no. 8, pp. 1928–1942, 2001.
View at: Publisher Site | Google Scholar
I. Antonucci, L. Stuppia, Y. Kaneko et al., “Amniotic fluid as a rich source of mesenchymal stromal cells for transplantation therapy,” Cell transplantation, vol. 20, no. 6, pp. 789–796, 2011.
View at: Publisher Site | Google Scholar
Y. Fukuchi, H. Nakajima, D. Sugiyama, I. Hirose, T. Kitamura, and K. Tsuji, “Human placenta-derived cells have mesenchymal stem/progenitor cell potential,” Stem Cells, vol. 22, no. 5, pp. 649–658, 2004.
View at: Publisher Site | Google Scholar
F. J. Lv, R. S. Tuan, K. M. Cheung, and V. Y. Leung, “Concise review: the surface markers and identity of human mesenchymal stem cells,” Stem Cells, vol. 32, no. 6, pp. 1408–1419, 2014.
View at: Publisher Site | Google Scholar
C. Li, G. Wei, Q. Gu et al., “Donor age and cell passage affect osteogenic ability of rat bone marrow mesenchymal stem cells,” Cell Biochemistry and Biophysics, vol. 72, no. 2, pp. 543–549, 2015.
View at: Publisher Site | Google Scholar
X. Yi, F. Chen, F. Liu et al., “Comparative separation methods and biological characteristics of human placental and umbilical cord mesenchymal stem cells in serum-free culture conditions,” Stem cell research & therapy, vol. 11, no. 1, p. 183, 2020.
View at: Publisher Site | Google Scholar
L. T. Nguyen, N. T. Tran, U. T. T. Than et al., “Optimization of human umbilical cord blood-derived mesenchymal stem cell isolation and culture methods in serum- and xeno-free conditions,” Stem cell research & therapy, vol. 13, no. 1, p. 15, 2022.
View at: Publisher Site | Google Scholar
S. Kern, H. Eichler, J. Stoeve, H. Klüter, and K. Bieback, “Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue,” Stem Cells, vol. 24, no. 5, pp. 1294–1301, 2006.
View at: Publisher Site | Google Scholar
J. S. Heo, Y. Choi, H. S. Kim, and H. O. Kim, “Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue,” International journal of molecular medicine, vol. 37, no. 1, pp. 115–125, 2016.
View at: Publisher Site | Google Scholar
M. Wu, R. Zhang, Q. Zou et al., “Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord,” Scientific Reports, vol. 8, no. 1, p. 5014, 2018.
View at: Publisher Site | Google Scholar
S. Diederichs and R. S. Tuan, “Functional comparison of human-induced pluripotent stem cell-derived mesenchymal cells and bone marrow-derived mesenchymal stromal cells from the same donor,” Stem Cells and Development, vol. 23, no. 14, pp. 1594–1610, 2014.
View at: Publisher Site | Google Scholar
A. J. Friedenstein, J. F. Gorskaja, and N. N. Kulagina, “Fibroblast precursors in normal and irradiated mouse hematopoietic organs,” Experimental hematology, vol. 4, no. 5, pp. 267–274, 1976.
View at: Google Scholar
D. J. Prockop, “Marrow stromal cells as stem cells for nonhematopoietic tissues,” Science, vol. 276, no. 5309, pp. 71–74, 1997.
View at: Publisher Site | Google Scholar
A. I. Caplan, “Mesenchymal stem cells,” Journal of orthopaedic research, vol. 9, no. 5, pp. 641–650, 1991.
View at: Publisher Site | Google Scholar
D. C. Ding, Y. H. Chang, W. C. Shyu, and S. Z. Lin, “Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy,” Cell Transplant, vol. 24, no. 3, pp. 339–347, 2015.
View at: Publisher Site | Google Scholar
D. Minteer, K. G. Marra, and J. P. Rubin, “Adipose-derived mesenchymal stem cells: biology and potential applications,” Advances in Biochemical Engineering/Biotechnology, vol. 129, pp. 59–71, 2013.
View at: Publisher Site | Google Scholar
B. Naughton, “Cells isolated from Wharton's jelly of the human umbilical cord develop a cartilage phenotype when treated with TGFβ in vitro,” The FASEB Journal, vol. 11, p. A19, 1997.
View at: Google Scholar
R. Sarugaser, D. Lickorish, D. Baksh, M. M. Hosseini, and J. E. Davies, “Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors,” Stem Cells, vol. 23, no. 2, pp. 220–229, 2005.
View at: Publisher Site | Google Scholar
X. Fang, L. Liu, J. Dong et al., “A study about immunomodulatory effect and efficacy and prognosis of human umbilical cord mesenchymal stem cells in patients with chronic hepatitis B-induced decompensated liver cirrhosis,” Journal of gastroenterology and hepatology, vol. 33, no. 4, pp. 774–780, 2018.
View at: Publisher Site | Google Scholar
P. A. Zuk, M. Zhu, P. Ashjian et al., “Human adipose tissue is a source of multipotent stem cells,” Molecular biology of the cell, vol. 13, no. 12, pp. 4279–4295, 2002.
View at: Publisher Site | Google Scholar
J. K. Fraser, I. Wulur, Z. Alfonso, and M. H. Hedrick, “Fat tissue: an underappreciated source of stem cells for biotechnology,” Trends in biotechnology, vol. 24, no. 4, pp. 150–154, 2006.
View at: Google Scholar
Q. Lian, Y. Zhang, J. Zhang et al., “Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice,” Circulation, vol. 121, no. 9, pp. 1113–1123, 2010.
View at: Publisher Site | Google Scholar
Y. Lei and D. V. Schaffer, “A fully defined and scalable 3D culture system for human pluripotent stem cell expansion and differentiation,” Proceedings of the National Academy of Sciences, vol. 110, no. 52, pp. E5039–E5048, 2013.
View at: Publisher Site | Google Scholar
M. A. Khan, F. Alanazi, H. A. Ahmed et al., “iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants,” Stem cell research & therapy, vol. 10, no. 1, p. 290, 2019.
View at: Publisher Site | Google Scholar
C. L. Li, Y. Leng, B. Zhao et al., “Human iPSC-MSC-derived xenografts modulate immune responses by inhibiting the cleavage of caspases,” Stem Cells, vol. 35, no. 7, pp. 1719–1732, 2017.
View at: Publisher Site | Google Scholar
X. Qi, K. T. Ng, Q. Lian et al., “Glutathione peroxidase 3 delivered by hiPSC-MSCs ameliorated hepatic IR injury via inhibition of hepatic senescence,” Theranostics, vol. 8, no. 1, pp. 212–222, 2018.
View at: Publisher Site | Google Scholar
X. Li, Y. Zhang, Y. Liang et al., “iPSC-derived mesenchymal stem cells exert SCF-dependent recovery of cigarette smoke-induced apoptosis/proliferation imbalance in airway cells,” Journal of Cellular and Molecular Medicine, vol. 21, no. 2, pp. 265–277, 2017.
View at: Publisher Site | Google Scholar
K. Akiyama, C. Chen, D. Wang et al., “Mesenchymal-Stem-Cell-Induced Immunoregulation Involves FAS-Ligand-/FAS- Mediated T Cell Apoptosis,” Cell Stem Cell, vol. 10, no. 5, pp. 544–555, 2012.
View at: Publisher Site | Google Scholar
X. Li, Y. Hong, H. He et al., “FGF21 mediates mesenchymal stem cell senescence via regulation of mitochondrial dynamics,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 4915149, 13 pages, 2019.
View at: Publisher Site | Google Scholar
A. J. C. Bloor, A. Patel, J. E. Griffin et al., “Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study,” Nature Medicine, vol. 26, no. 11, pp. 1720–1725, 2020.
View at: Publisher Site | Google Scholar
J. Wang, P. Cen, J. Chen et al., “Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure,” Stem cell research & therapy, vol. 8, no. 1, p. 137, 2017.
View at: Publisher Site | Google Scholar
W. H. Liu, F. Q. Song, L. N. Ren et al., “The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases,” Journal of cellular and molecular medicine, vol. 19, no. 3, pp. 511–520, 2015.
View at: Publisher Site | Google Scholar
Y. Han, J. Yang, J. Fang et al., “The secretion profile of mesenchymal stem cells and potential applications in treating human diseases,” Signal Transduction and Targeted Therapy, vol. 7, no. 1, p. 92, 2022.
View at: Publisher Site | Google Scholar
Y. Liang, L. Duan, J. Lu, and J. Xia, “Engineering exosomes for targeted drug delivery,” Theranostics, vol. 11, no. 7, pp. 3183–3195, 2021.
View at: Publisher Site | Google Scholar
G. Lou, Z. Chen, M. Zheng, and Y. Liu, “Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases,” Experimental & molecular medicine, vol. 49, no. 6, article e346, 2017.
View at: Publisher Site | Google Scholar
W. Jiang, Y. Tan, M. Cai et al., “Human umbilical cord MSC-derived exosomes suppress the development of CCl(4)-induced liver injury through antioxidant effect,” Stem Cells International, vol. 2018, Article ID 6079642, 11 pages, 2018.
View at: Publisher Site | Google Scholar
T. Li, Y. Yan, B. Wang et al., “Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis,” Stem cells and development, vol. 22, no. 6, pp. 845–854, 2013.
View at: Publisher Site | Google Scholar
X. Rong, J. Liu, X. Yao, T. Jiang, Y. Wang, and F. Xie, “Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway,” Stem Cell Research & Therapy, vol. 10, no. 1, p. 98, 2019.
View at: Publisher Site | Google Scholar
J. Wang, C. Bian, L. Liao et al., “Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms,” Hepatology Research, vol. 39, no. 12, pp. 1219–1228, 2009.
View at: Publisher Site | Google Scholar
N. Lin, K. Hu, S. Chen et al., “Nerve growth factor-mediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells,” Life sciences, vol. 85, no. 7-8, pp. 291–295, 2009.
View at: Publisher Site | Google Scholar
S. Y. An, Y. J. Jang, H. J. Lim et al., “Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice,” Gastroenterology, vol. 152, no. 5, pp. 1174–1186, 2017.
View at: Publisher Site | Google Scholar
J. S. Choi, Y. J. Park, and S. W. Kim, “Three-dimensional differentiated human mesenchymal stem cells exhibit robust antifibrotic potential and ameliorates mouse liver fibrosis,” Cell Transplant, vol. 30, 2021.
View at: Google Scholar
B. Parekkadan, D. van Poll, Z. Megeed et al., “Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells,” Biochemical and biophysical research communications, vol. 363, no. 2, pp. 247–252, 2007.
View at: Publisher Site | Google Scholar
M. W. Robinson, C. Harmon, and C. O'Farrelly, “Liver immunology and its role in inflammation and homeostasis,” Cellular & molecular immunology, vol. 13, no. 3, pp. 267–276, 2016.
View at: Publisher Site | Google Scholar
Y. Cao, C. Ji, and L. Lu, “Mesenchymal stem cell therapy for liver fibrosis/cirrhosis,” Annals of translational medicine, vol. 8, no. 8, p. 562, 2020.
View at: Publisher Site | Google Scholar
D. Wang, H. Zhang, J. Liang et al., “Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI: C-induced primary biliary cirrhosis mouse model,” Clinical and experimental medicine, vol. 11, no. 1, pp. 25–32, 2011.
View at: Publisher Site | Google Scholar
N. Milosavljevic, M. Gazdic, B. Simovic Markovic et al., “Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells - an experimental study,” Transplant international, vol. 31, no. 1, pp. 102–115, 2018.
View at: Publisher Site | Google Scholar
A. Seki, Y. Sakai, T. Komura et al., “Adipose tissue-derived stem cells as a regenerative therapy for a mouse steatohepatitis-induced cirrhosis model,” Hepatology, vol. 58, no. 3, pp. 1133–1142, 2013.
View at: Publisher Site | Google Scholar
L. Wang, Q. Han, H. Chen et al., “Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis,” Stem cells and development, vol. 23, no. 20, pp. 2482–2489, 2014.
View at: Publisher Site | Google Scholar
L. Xu, Y. Gong, B. Wang et al., “Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/Th17 cells,” Journal of Gastroenterology and Hepatology, vol. 29, no. 8, pp. 1620–1628, 2014.
View at: Publisher Site | Google Scholar
S. Kumar, Q. Duan, R. Wu, E. N. Harris, and Q. Su, “Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis,” Advanced Drug Delivery Reviews, vol. 176, article 113869, 2021.
View at: Publisher Site | Google Scholar
T. Luangmonkong, S. Suriguga, H. A. M. Mutsaers, G. M. M. Groothuis, P. Olinga, and M. Boersema, “Targeting oxidative stress for the treatment of liver fibrosis,” Reviews of Physiology, Biochemistry and Pharmacology, vol. 175, pp. 71–102, 2018.
View at: Publisher Site | Google Scholar
S. Gaul, A. Leszczynska, F. Alegre et al., “Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis,” Journal of hepatology, vol. 74, no. 1, pp. 156–167, 2021.
View at: Publisher Site | Google Scholar
A. Afshari, S. Shamdani, G. Uzan, S. Naserian, and N. Azarpira, “Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells,” Stem cell research & therapy, vol. 11, no. 1, p. 54, 2020.
View at: Publisher Site | Google Scholar
J. Wang, L. Xu, Q. Chen, Y. Zhang, Y. Hu, and L. Yan, “Bone mesenchymal stem cells overexpressing FGF4 contribute to liver regeneration in an animal model of liver cirrhosis,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 8, pp. 12774–12782, 2015.
View at: Google Scholar
P. Salehinejad, N. B. Alitheen, A. Mandegary, S. N. Nematollahi-Mahani, and E. Janzamin, “Effect of EGF and FGF on the expansion properties of human umbilical cord mesenchymal cells,” In Vitro Cellular & Developmental Biology-Animal, vol. 49, no. 7, pp. 515–523, 2013.
View at: Publisher Site | Google Scholar
X. Wei, C. Y. Wang, Q. P. Liu et al., “In vitro hepatic differentiation of mesenchymal stem cells from human fetal bone marrow,” Journal of International Medical Research, vol. 36, no. 4, pp. 721–727, 2008.
View at: Publisher Site | Google Scholar
Y. Xiang, B. Y. Pang, Y. Zhang et al., “Effect of Yi Guan Jian decoction on differentiation of bone marrow mesenchymalstem cells into hepatocyte-like cells in dimethylnitrosamine-induced liver cirrhosis in mice,” Molecular Medicine Reports, vol. 15, no. 2, pp. 613–626, 2017.
View at: Publisher Site | Google Scholar
L. Fu, B. Pang, Y. Zhu, L. Wang, A. Leng, and H. Chen, “Ex vivo stromal cell-derived factor 1-mediated differentiation of mouse bone marrow mesenchymal stem cells into hepatocytes is enhanced by Chinese medicine Yiguanjian drug-containing serum,” Evidence-Based Complementary and Alternative Medicine, vol. 2016, Article ID 7380439, 12 pages, 2016.
View at: Publisher Site | Google Scholar
S. Jin, H. Li, M. Han et al., “Mesenchymal stem cells with enhanced Bcl-2 expression promote liver recovery in a rat model of hepatic cirrhosis,” Cellular Physiology and Biochemistry, vol. 40, no. 5, pp. 1117–1128, 2016.
View at: Publisher Site | Google Scholar
C. Lange, P. Bassler, M. V. Lioznov et al., “Liver-specific gene expression in mesenchymal stem cells is induced by liver cells,” World journal of gastroenterology, vol. 11, no. 29, pp. 4497–4504, 2005.
View at: Publisher Site | Google Scholar
Y. C. Wu, G. X. Wu, K. W. Chen et al., “Transplantation of 3D adipose-derived stem cell/hepatocyte spheroids alleviates chronic hepatic damage in a rat model of thioacetamide-induced liver cirrhosis,” Scientific Reports, vol. 12, no. 1, p. 1227, 2022.
View at: Publisher Site | Google Scholar
S. Y. Ong, H. Dai, and K. W. Leong, “Inducing hepatic differentiation of human mesenchymal stem cells in pellet culture,” Biomaterials, vol. 27, no. 22, pp. 4087–4097, 2006.
View at: Publisher Site | Google Scholar
J. Hong, H. Jin, J. Han et al., “Infusion of human umbilical cord-derived mesenchymal stem cells effectively relieves liver cirrhosis in DEN-induced rats,” Molecular Medicine Reports, vol. 9, no. 4, pp. 1103–1111, 2014.
View at: Publisher Site | Google Scholar
C. Hu, L. Zhao, J. Duan, and L. Li, “Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis,” Journal of Cellular and Molecular Medicine, vol. 23, no. 3, pp. 1657–1670, 2019.
View at: Publisher Site | Google Scholar
H. E. Mohamed, S. E. Elswefy, L. A. Rashed, N. N. Younis, M. A. Shaheen, and A. M. Ghanim, “Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model,” Experimental Biology and Medicine, vol. 241, no. 6, pp. 581–591, 2016.
View at: Publisher Site | Google Scholar
S. M. Khadrawy, H. M. Mohamed, and A. M. Mahmoud, “Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats,” Environmental Science and Pollution Research, vol. 28, no. 2, pp. 2019–2030, 2021.
View at: Publisher Site | Google Scholar
K. A. Cho, S. Y. Woo, J. Y. Seoh, H. S. Han, and K. H. Ryu, “Mesenchymal stem cells restore CCl4-induced liver injury by an antioxidative process,” Cell biology international, vol. 36, no. 12, pp. 1267–1274, 2012.
View at: Publisher Site | Google Scholar
R. Sasaki, T. Takami, K. Fujisawa et al., “Trans-portal hepatic infusion of cultured bone marrow-derived mesenchymal stem cells in a steatohepatitis murine model,” Journal of clinical biochemistry and nutrition, vol. 67, no. 3, pp. 274–282, 2020.
View at: Publisher Site | Google Scholar
M. Ayatollahi, Z. Hesami, A. Jamshidzadeh, and B. Gramizadeh, “Antioxidant effects of bone marrow mesenchymal stem cell against carbon tetrachloride-induced oxidative damage in rat livers,” International journal of organ transplantation medicine, vol. 5, no. 4, pp. 166–173, 2014.
View at: Google Scholar
G. Pietrosi, A. Fernández-Iglesias, M. Pampalone et al., “Human amniotic stem cells improve hepatic microvascular dysfunction and portal hypertension in cirrhotic rats,” Liver international, vol. 40, no. 10, pp. 2500–2514, 2020.
View at: Publisher Site | Google Scholar
S. J. Dixon, K. M. Lemberg, M. R. Lamprecht et al., “Ferroptosis: an iron-dependent form of nonapoptotic cell death,” Cell, vol. 149, no. 5, pp. 1060–1072, 2012.
View at: Publisher Site | Google Scholar
A. Weiland, Y. Wang, W. Wu et al., “Ferroptosis and its role in diverse brain diseases,” Molecular Neurobiology, vol. 56, no. 7, pp. 4880–4893, 2019.
View at: Publisher Site | Google Scholar
X. Chen, R. Kang, G. Kroemer, and D. Tang, “Broadening horizons: the role of ferroptosis in cancer,” Nature reviews Clinical oncology, vol. 18, no. 5, pp. 280–296, 2021.
View at: Publisher Site | Google Scholar
T. Bai, P. Lei, H. Zhou et al., “Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells,” Journal of cellular and molecular medicine, vol. 23, no. 11, pp. 7349–7359, 2019.
View at: Publisher Site | Google Scholar
Y. Tan, Y. Huang, R. Mei et al., “HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis,” Cell death & disease, vol. 13, no. 4, p. 319, 2022.
View at: Publisher Site | Google Scholar
B. Levine and G. Kroemer, “Biological functions of autophagy genes: a disease perspective,” Cell, vol. 176, no. 1-2, pp. 11–42, 2019.
View at: Publisher Site | Google Scholar
D. J. Klionsky, G. Petroni, R. K. Amaravadi et al., “Autophagy in major human diseases,” The EMBO journal, vol. 40, no. 19, article e108863, 2021.
View at: Publisher Site | Google Scholar
Y. Qu, Q. Zhang, X. Cai et al., “Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation,” Journal of cellular and molecular medicine, vol. 21, no. 10, pp. 2491–2502, 2017.
View at: Publisher Site | Google Scholar
M. Zhu, X. Liu, W. Li, and L. Wang, “Exosomes derived from mmu_circ_0000623-modified ADSCs prevent liver fibrosis via activating autophagy,” Human & Experimental Toxicology, vol. 39, no. 12, pp. 1619–1627, 2020.
View at: Publisher Site | Google Scholar
M. Park, Y. H. Kim, S. Y. Woo et al., “Tonsil-derived mesenchymal stem cells ameliorate CCl₄-induced liver fibrosis in mice via autophagy activation,” Scientific reports, vol. 5, no. 1, p. 8616, 2015.
View at: Publisher Site | Google Scholar
M. J. Hsu, I. Karkossa, I. Schäfer et al., “Mitochondrial transfer by human mesenchymal stromal cells ameliorates hepatocyte lipid load in a mouse model of NASH,” Biomedicines, vol. 8, no. 9, p. 350, 2020.
View at: Publisher Site | Google Scholar
Y. Zhang, Z. Yu, D. Jiang 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, vol. 7, no. 4, pp. 749–763, 2016.
View at: Publisher Site | Google Scholar
K. Piekarska, Z. Urban-Wójciuk, M. Kurkowiak et al., “Mesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA- dependent manner improving their immunosuppressive activity,” Nature Communications, vol. 13, no. 1, p. 856, 2022.
View at: Publisher Site | Google Scholar
X. Li, Y. Zhang, S. C. Yeung et al., “Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage,” American Journal of Respiratory Cell and Molecular Biology, vol. 51, no. 3, pp. 455–465, 2014.
View at: Publisher Site | Google Scholar
A. C. Court, A. Le-Gatt, P. Luz-Crawford et al., “Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response,” EMBO Reports, vol. 21, no. 2, article e48052, 2020.
View at: Publisher Site | Google Scholar
S. Schuster, D. Cabrera, M. Arrese, and A. E. Feldstein, “Triggering and resolution of inflammation in NASH,” Nature reviews Gastroenterology & hepatology, vol. 15, no. 6, pp. 349–364, 2018.
View at: Publisher Site | Google Scholar
E. M. Brunt, V. W. Wong, V. Nobili et al., “Nonalcoholic fatty liver disease,” Nature Reviews Disease Primers, vol. 1, no. 1, p. 15080, 2015.
View at: Publisher Site | Google Scholar
P. Bedossa, “Pathology of non-alcoholic fatty liver disease,” Liver International, vol. 37, Supplement 1, pp. 85–89, 2017.
View at: Publisher Site | Google Scholar
D. A. Vignali, L. W. Collison, and C. J. Workman, “How regulatory T cells work,” Nature Reviews Immunology, vol. 8, no. 7, pp. 523–532, 2008.
View at: Publisher Site | Google Scholar
Y. Ikeno, D. Ohara, Y. Takeuchi et al., “Foxp3+ regulatory T cells inhibit CCl4-Induced liver inflammation and fibrosis by regulating tissue cellular immunity,” Frontiers in immunology, vol. 11, article 584048, 2020.
View at: Publisher Site | Google Scholar
H. Yang, R. Feng, Q. Fu et al., “Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF-α-stimulated gene-6 in inflammatory bowel disease models,” Cell death & disease, vol. 10, no. 10, p. 718, 2019.
View at: Publisher Site | Google Scholar
Y. Yao, X. L. Fan, D. Jiang et al., “Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation,” Stem Cell Reports, vol. 11, no. 5, pp. 1120–1135, 2018.
View at: Publisher Site | Google Scholar
S. Thavapalachandran, T. Y. L. Le, S. Romanazzo et al., “Pluripotent stem cell-derived mesenchymal stromal cells improve cardiac function and vascularity after myocardial infarction,” Cytotherapy, vol. 23, no. 12, pp. 1074–1084, 2021.
View at: Publisher Site | Google Scholar
H. Yang, R. M. Aprecio, X. Zhou et al., “Therapeutic effect of TSG-6 engineered iPSC-derived MSCs on experimental periodontitis in rats: a pilot study,” PLoS One, vol. 9, no. 6, article e100285, 2014.
View at: Publisher Site | Google Scholar
K. Hynes, D. Menicanin, J. Han et al., “Mesenchymal stem cells from iPS cells facilitate periodontal regeneration,” Journal of dental research, vol. 92, no. 9, pp. 833–839, 2013.
View at: Publisher Site | Google Scholar
Q. Zhao, B. Hai, J. Kelly, S. Wu, and F. Liu, “Extracellular vesicle mimics made from iPS cell-derived mesenchymal stem cells improve the treatment of metastatic prostate cancer,” Stem Cell Research & Therapy, vol. 12, no. 1, p. 29, 2021.
View at: Publisher Site | Google Scholar
Q. Zhao, B. Hai, X. Zhang, J. Xu, B. Koehler, and F. Liu, “Biomimetic nanovesicles made from iPS cell-derived mesenchymal stem cells for targeted therapy of triple-negative breast cancer,” Nanomedicine, vol. 24, article 102146, 2020.
View at: Publisher Site | Google Scholar
H. Zhong, X. L. Fan, S. B. Fang, Y. D. Lin, W. Wen, and Q. L. Fu, “Human pluripotent stem cell-derived mesenchymal stem cells prevent chronic allergic airway inflammation via TGF-β1-Smad2/Smad3 signaling pathway in mice,” Molecular Immunology, vol. 109, pp. 51–57, 2019.
View at: Publisher Site | Google Scholar
Y. Yang, G. Ye, Y. L. Zhang et al., “Transfer of mitochondria from mesenchymal stem cells derived from induced pluripotent stem cells attenuates hypoxia-ischemia-induced mitochondrial dysfunction in PC12 cells,” Neural Regeneration Research, vol. 15, no. 3, pp. 464–472, 2020.
View at: Publisher Site | Google Scholar
S. Keshtkar, N. Azarpira, and M. H. Ghahremani, “Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine,” Stem cell research & therapy, vol. 9, no. 1, p. 63, 2018.
View at: Publisher Site | Google Scholar
J. Galipeau and L. Sensébé, “Mesenchymal stromal cells: clinical challenges and therapeutic opportunities,” Cell Stem Cell, vol. 22, no. 6, pp. 824–833, 2018.
View at: Publisher Site | Google Scholar
M. Shi, Y. Y. Li, R. N. Xu et al., “Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial,” Hepatology International, vol. 15, no. 6, pp. 1431–1441, 2021.
View at: Publisher Site | Google Scholar
Z. Zhang, H. Lin, M. Shi et al., “Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients,” Journal of gastroenterology and hepatology, vol. 27, Supplement 2, pp. 112–120, 2012.
View at: Publisher Site | Google Scholar
J. Liang, H. Zhang, C. Zhao et al., “Effects of allogeneic mesenchymal stem cell transplantation in the treatment of liver cirrhosis caused by autoimmune diseases,” International Journal of Rheumatic Diseases, vol. 20, no. 9, pp. 1219–1226, 2017.
View at: Publisher Site | Google Scholar
M. Mohamadnejad, K. Alimoghaddam, M. Mohyeddin-Bonab et al., “Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis,” Archives of Iranian Medicine, vol. 10, no. 4, pp. 459–466, 2007.
View at: Publisher Site | Google Scholar
M. Mohamadnejad, K. Alimoghaddam, M. Bagheri et al., “Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis,” Liver International, vol. 33, no. 10, pp. 1490–1496, 2013.
View at: Publisher Site | Google Scholar
P. Kharaziha, P. M. Hellström, B. Noorinayer et al., “Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial,” European journal of gastroenterology & hepatology, vol. 21, no. 10, pp. 1199–1205, 2009.
View at: Publisher Site | Google Scholar
K. C. Huang, M. H. Chuang, Z. S. Lin et al., “Transplantation with GXHPC1 for liver cirrhosis: phase 1 trial,” Cell Transplant, vol. 28, no. 1, pp. 100s–111s, 2019.
View at: Publisher Site | Google Scholar
K. T. Suk, J. H. Yoon, M. Y. Kim et al., “Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial,” Hepatology, vol. 64, no. 6, pp. 2185–2197, 2016.
View at: Publisher Site | Google Scholar
L. Wang, J. Li, H. Liu et al., “A Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis,” Journal of gastroenterology and hepatology, vol. 28, Supplement 1, pp. 85–92, 2013.
View at: Publisher Site | Google Scholar
M. El-Ansary, I. Abdel-Aziz, S. Mogawer et al., “Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis,” Stem Cell Reviews and Reports, vol. 8, no. 3, pp. 972–981, 2012.
View at: Publisher Site | Google Scholar
H. Salama, A. R. Zekri, E. Medhat et al., “Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease,” Stem Cell Research & Therapy, vol. 5, no. 3, p. 70, 2014.
View at: Publisher Site | Google Scholar
Y. O. Jang, Y. J. Kim, S. K. Baik et al., “Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study,” Liver International, vol. 34, no. 1, pp. 33–41, 2014.
View at: Publisher Site | Google Scholar
C. Hu, L. Zhao, and L. Li, “Genetic modification by overexpression of target gene in mesenchymal stromal cell for treating liver diseases,” Journal of Molecular Medicine, vol. 99, no. 2, pp. 179–192, 2021.
View at: Publisher Site | Google Scholar
J. B. Aquino, M. F. Bolontrade, M. G. García, O. L. Podhajcer, and G. Mazzolini, “Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma,” Gene therapy, vol. 17, no. 6, pp. 692–708, 2010.
View at: Publisher Site | Google Scholar
C. Du, M. Jiang, X. Wei et al., “Transplantation of human matrix metalloproteinase-1 gene-modified bone marrow-derived mesenchymal stem cell attenuates CCL4-induced liver fibrosis in rats,” International Journal of Molecular Medicine, vol. 41, no. 6, pp. 3175–3184, 2018.
View at: Publisher Site | Google Scholar
G. Lou, Y. Yang, F. Liu et al., “MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis,” Journal of Cellular and Molecular Medicine, vol. 21, no. 11, pp. 2963–2973, 2017.
View at: Publisher Site | Google Scholar
X. Wang, H. Wang, J. Lu et al., “Erythropoietin-modified mesenchymal stem cells enhance anti-fibrosis efficacy in mouse liver fibrosis model,” Tissue Engineering and Regenerative Medicine, vol. 17, no. 5, pp. 683–693, 2020.
View at: Publisher Site | Google Scholar
J. Zhang, S. Zhou, Y. Zhou et al., “Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model,” PLoS One, vol. 9, no. 12, article e114670, 2014.
View at: Publisher Site | Google Scholar
K. W. Seo, S. Y. Sohn, D. H. Bhang, M. J. Nam, H. W. Lee, and H. Y. Youn, “Therapeutic effects of hepatocyte growth factor-overexpressing human umbilical cord blood-derived mesenchymal stem cells on liver fibrosis in rats,” Cell Biology International, vol. 38, no. 1, pp. 106–116, 2014.
View at: Publisher Site | Google Scholar
E. J. Fiore, J. M. Bayo, M. G. Garcia et al., “Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice,” Stem cells and development, vol. 24, no. 6, pp. 791–801, 2015.
View at: Publisher Site | Google Scholar
D. N. Su, S. P. Wu, and S. Z. Xu, “Mesenchymal stem cell-based Smad7 gene therapy for experimental liver cirrhosis,” Stem cell research & therapy, vol. 11, no. 1, p. 395, 2020.
View at: Publisher Site | Google Scholar
Z. Ye, W. Lu, L. Liang et al., “Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice,” Stem Cell Research & Therapy, vol. 10, no. 1, p. 149, 2019.
View at: Publisher Site | Google Scholar
Q. Liu, C. Lv, Q. Huang et al., “ECM1 modified HF-MSCs targeting HSC attenuate liver cirrhosis by inhibiting the TGF-β/Smad signaling pathway,” Cell Death Discovery, vol. 8, no. 1, p. 51, 2022.
View at: Publisher Site | Google Scholar
S. Robert, T. Gicquel, T. Victoni et al., “Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis,” Bioscience reports, vol. 36, no. 4, 2016.
View at: Publisher Site | Google Scholar
A. I. Masyuk, T. V. Masyuk, and N. F. Larusso, “Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases,” Journal of Hepatology, vol. 59, no. 3, pp. 621–625, 2013.
View at: Publisher Site | Google Scholar
S. Nakamura, M. Sho, F. Koyama et al., “Erythropoietin attenuates intestinal inflammation and promotes tissue regeneration,” Scandinavian Journal of Gastroenterology, vol. 50, no. 9, pp. 1094–1102, 2015.
View at: Publisher Site | Google Scholar
J. Auzmendi, M. B. Puchulu, J. C. G. Rodríguez, A. M. Balaszczuk, A. Lazarowski, and A. Merelli, “EPO and EPO-receptor system as potential actionable mechanism for the protection of brain and heart in refractory epilepsy and SUDEP,” Current Pharmaceutical Design, vol. 26, no. 12, pp. 1356–1364, 2020.
View at: Publisher Site | Google Scholar
L. N. Chen, Q. Sun, S. Q. Liu et al., “Erythropoietin improves glucose metabolism and pancreatic β-cell damage in experimental diabetic rats,” Molecular Medicine Reports, vol. 12, no. 4, pp. 5391–5398, 2015.
View at: Publisher Site | Google Scholar
J. Li, T. Tao, J. Xu, Z. Liu, Z. Zou, and M. Jin, “HIF-1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia-reperfusion injury in a rat MCAO model,” International Journal of Molecular Medicine, vol. 45, no. 4, pp. 1027–1036, 2020.
View at: Publisher Site | Google Scholar
G. Michalopoulos, K. A. Houck, M. L. Dolan, and N. C. Leutteke, “Control of hepatocyte replication by two serum factors,” Cancer research, vol. 44, no. 10, pp. 4414–4419, 1984.
View at: Google Scholar
M. Sato, M. Kakubari, M. Kawamura, J. Sugimoto, K. Matsumoto, and T. Ishii, “The decrease in total collagen fibers in the liver by hepatocyte growth factor after formation of cirrhosis induced by thioacetamide,” Biochemical Pharmacology, vol. 59, no. 6, pp. 681–690, 2000.
View at: Publisher Site | Google Scholar
F. He, L. X. Wu, K. X. Shu et al., “HGF protects cultured cortical neurons against hypoxia/reoxygenation induced cell injury via ERK1/2 and PI-3K/Akt pathways,” Colloids Surf B Biointerfaces, vol. 61, no. 2, pp. 290–297, 2008.
View at: Publisher Site | Google Scholar
G. Son, I. N. Hines, J. Lindquist, L. W. Schrum, and R. A. Rippe, “Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis,” Hepatology, vol. 50, no. 5, pp. 1512–1523, 2009.
View at: Publisher Site | Google Scholar
K. Bonefeld and S. Møller, “Insulin-like growth factor-I and the liver,” Liver International, vol. 31, no. 7, pp. 911–919, 2011.
View at: Publisher Site | Google Scholar
X. Coumoul and C. X. Deng, “Roles of FGF receptors in mammalian development and congenital diseases,” Birth Defects Research Part C: Embryo Today: Reviews, vol. 69, no. 4, pp. 286–304, 2003.
View at: Publisher Site | Google Scholar
X. Zhang, O. A. Ibrahimi, S. K. Olsen, H. Umemori, M. Mohammadi, and D. M. Ornitz, “Receptor specificity of the fibroblast growth factor family: The complete mammalian FGF family,” Journal of Biological Chemistry, vol. 281, no. 23, pp. 15694–15700, 2006.
View at: Google Scholar
J. Farré, S. Roura, C. Prat-Vidal et al., “FGF-4 increases in vitro expansion rate of human adult bone marrow-derived mesenchymal stem cells,” Growth Factors, vol. 25, no. 2, pp. 71–76, 2007.
View at: Publisher Site | Google Scholar
S. C. Choi, S. J. Kim, J. H. Choi, C. Y. Park, W. J. Shim, and D. S. Lim, “Fibroblast growth factor-2 and -4 promote the proliferation of bone marrow mesenchymal stem cells by the activation of the PI3K-Akt and ERK1/2 signaling pathways,” Stem cells and development, vol. 17, no. 4, pp. 725–736, 2008.
View at: Publisher Site | Google Scholar
F. Xu, C. Liu, D. Zhou, and L. Zhang, “TGF-β/SMAD pathway and its regulation in hepatic fibrosis,” Journal of Histochemistry and Cytochemistry, vol. 64, no. 3, pp. 157–167, 2016.
View at: Publisher Site | Google Scholar
A. J. Watt, W. D. Garrison, and S. A. Duncan, “HNF4: a central regulator of hepatocyte differentiation and function,” Hepatology, vol. 37, no. 6, pp. 1249–1253, 2003.
View at: Publisher Site | Google Scholar
F. Parviz, C. Matullo, W. D. Garrison et al., “Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis,” Nature genetics, vol. 34, no. 3, pp. 292–296, 2003.
View at: Publisher Site | Google Scholar
W. Fan, T. Liu, W. Chen et al., “ECM1 prevents activation of transforming growth factor β, hepatic stellate cells, and fibrogenesis in mice,” Gastroenterology, vol. 157, no. 5, pp. 1352–1367.e13, 2019.
View at: Publisher Site | Google Scholar
M. T. Baig, H. Ghufran, A. Mehmood, M. Azam, S. Humayun, and S. Riazuddin, “Vitamin E pretreated Wharton's jelly-derived mesenchymal stem cells attenuate CCl₄-induced hepatocyte injury in vitro and liver fibrosis in vivo,” Biochemical Pharmacology, vol. 186, article 114480, 2021.
View at: Publisher Site | Google Scholar
R. Hardeland, “Aging, melatonin, and the pro- and anti-inflammatory networks,” International Journal of Molecular Sciences, vol. 20, no. 5, p. 1223, 2019.
View at: Publisher Site | Google Scholar
K. Mortezaee, P. Pasbakhsh, I. Ragerdi Kashani et al., “Melatonin pretreatment enhances the homing of bone marrow-derived mesenchymal stem cells following transplantation in a rat model of liver fibrosis,” Iranian biomedical journal, vol. 20, no. 4, pp. 207–216, 2016.
View at: Google Scholar
K. Mortezaee, N. Khanlarkhani, F. Sabbaghziarani et al., “Preconditioning with melatonin improves therapeutic outcomes of bone marrow-derived mesenchymal stem cells in targeting liver fibrosis induced by CCl4,” Cell and Tissue Research, vol. 369, no. 2, pp. 303–312, 2017.
View at: Publisher Site | Google Scholar
N. Liao, Y. Shi, Y. Wang et al., “Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model,” Stem cell research & therapy, vol. 11, no. 1, p. 237, 2020.
View at: Publisher Site | Google Scholar
H. Cui, Z. Liu, L. Wang et al., “Icariin-treated human umbilical cord mesenchymal stem cells decrease chronic liver injury in mice,” Cytotechnology, vol. 69, no. 1, pp. 19–29, 2017.
View at: Publisher Site | Google Scholar
S. Mohsin, S. Shams, G. Ali Nasir et al., “Enhanced hepatic differentiation of mesenchymal stem cells after pretreatment with injured liver tissue,” Differentiation, vol. 81, no. 1, pp. 42–48, 2011.
View at: Publisher Site | Google Scholar
Y. Qiao, Z. Xu, Y. Yu et al., “Single cell derived spheres of umbilical cord mesenchymal stem cells enhance cell stemness properties, survival ability and therapeutic potential on liver failure,” Biomaterials, vol. 227, article 119573, 2020.
View at: Publisher Site | Google Scholar
K. C. Murphy, A. I. Hoch, J. N. Harvestine, D. Zhou, and J. K. Leach, “Mesenchymal stem cell spheroids retain osteogenic phenotype through α2β1 signaling,” Stem cells translational medicine, vol. 5, no. 9, pp. 1229–1237, 2016.
View at: Publisher Site | Google Scholar
Y. Takahashi, R. Yuniartha, T. Yamaza et al., “Therapeutic potential of spheroids of stem cells from human exfoliated deciduous teeth for chronic liver fibrosis and hemophilia A,” Pediatric surgery international, vol. 35, no. 12, pp. 1379–1388, 2019.
View at: Publisher Site | Google Scholar
X. Zhang, M. G. Hu, K. Pan, C. H. Li, and R. Liu, “3D spheroid culture enhances the expression of antifibrotic factors in human adipose-derived MSCs and improves their therapeutic effects on hepatic fibrosis,” Stem Cells International, vol. 2016, Article ID 4626073, 8 pages, 2016.
View at: Publisher Site | Google Scholar
L. T. Wang, K. J. Liu, H. K. Sytwu, M. L. Yen, and B. L. Yen, “Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells,” Stem cells translational medicine, vol. 10, no. 9, pp. 1288–1303, 2021.
View at: Publisher Site | Google Scholar
H. Otera and K. Mihara, “Molecular mechanisms and physiologic functions of mitochondrial dynamics,” The Journal of Biochemistry, vol. 149, no. 3, pp. 241–251, 2011.
View at: Publisher Site | Google Scholar
B. Westermann, “Mitochondrial fusion and fission in cell life and death,” Nature reviews Molecular cell biology, vol. 11, no. 12, pp. 872–884, 2010.
View at: Publisher Site | Google Scholar
H. Otera, N. Ishihara, and K. Mihara, “New insights into the function and regulation of mitochondrial fission,” Biochimica et Biophysica Acta, vol. 1833, no. 5, pp. 1256–1268, 2013.
View at: Publisher Site | Google Scholar
M. F. Forni, J. Peloggia, K. Trudeau, O. Shirihai, and A. J. Kowaltowski, “Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics,” Stem Cells, vol. 34, no. 3, pp. 743–755, 2016.
View at: Publisher Site | Google Scholar
Y. S. Han, S. M. Kim, J. H. Lee, S. K. Jung, H. Noh, and S. H. Lee, “Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC-dependent enhancement of the mitochondrial function,” Journal of Pineal Research, vol. 66, no. 1, article e12535, 2019.
View at: Publisher Site | Google Scholar
M. Pasztorek, E. Rossmanith, C. Mayr et al., “Influence of platelet lysate on 2D and 3D amniotic mesenchymal stem cell cultures,” Frontiers in Bioengineering and Biotechnology, vol. 7, p. 338, 2019.
View at: Publisher Site | Google Scholar
W. Jin, X. Liang, A. Brooks et al., “Modelling of the SDF-1/CXCR4 regulatedin vivohoming of therapeutic mesenchymal stem/stromal cells in mice,” PeerJ, vol. 6, article e6072, 2018.
View at: Publisher Site | Google Scholar
Y. Shao, F. Zhou, D. He, L. Zhang, and J. Shen, “Overexpression of CXCR7 promotes mesenchymal stem cells to repair phosgene- induced acute lung injury in rats,” Biomedicine & Pharmacotherapy, vol. 109, pp. 1233–1239, 2019.
View at: Publisher Site | Google Scholar

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