Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu P
PROVIDER: S-EPMC9327386 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
Publications
Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential.
Liu Pinyan P Mao Yongcui Y Xie Ye Y Wei Jiayun J Yao Jia J
Stem cell research & therapy 20220726 1
Cost-effective treatment strategies for liver fibrosis or cirrhosis are limited. Many clinical trials of stem cells for liver disease shown that stem cells might be a potential therapeutic approach. This review will summarize the published clinical trials of stem cells for the treatment of liver fibrosis/cirrhosis and provide the latest overview of various cell sources, cell doses, and delivery methods. We also describe the limitations and strengths of various stem cells in clinical applications ...[more]
Similar Datasets
Project description:Human adipose-derived stem cells (hADSCs) are a promising source of autologous stem cells for personalized cell-based therapies. Culture expansion of ADSCs provides an attractive opportunity for liver cirrhosis patients. However, safety and stability issues can pose big challenges for personalized autologous stem cell products. In the present study, we addressed whether the commercial production program could provide a consistent product for liver cirrhosis therapy. We collected adipose tissue from three human donors by lipoaspirate and isolated ADSCs, which were expanded in culture to reach 1?×?108 cells (an approximately 1,000-fold expansion) within four passages. We then examined their morphology, chromosome stability, surface markers, and differentiation ability after culture. Next, we explored their therapeutic potential using a rat model of thioacetamide-induced liver cirrhosis. Culture-expanded ADSCs were injected intrahepatically, and their biodistribution was tracked by immunohistochemistry using an antibody against human mitochondria. Finally, we tested for tumor development by subcutaneously injecting a 100-fold dose range of cultured ADSCs into immunocompromised mice. Taken together, we find that culture expansion of autologous ADSCs is a potentially suitable stem cell product for personalized cell-based therapy for patients with liver cirrhosis.
| S-EPMC5657698 | biostudies-literature
Project description:BackgroundHigh mobility group proteins 1 and 2 (HMGB1 and HMGB2) are 80% conserved in amino acid sequence. The function of HMGB1 in inflammation and fibrosis has been extensively characterized. However, an unaddressed central question is the role of HMGB2 on liver fibrosis. In this study, we provided convincing evidence that the HMGB2 expression was significantly upregulated in human liver fibrosis and cirrhosis, as well as in several mouse liver fibrosis models.MethodsThe carbon tetrachloride (CCl4) induced liver fibrosis mouse model was used. AAV8-Hmgb2 was utilized to overexpress Hmgb2 in the liver, while Hmgb2-/- mice were used for loss of function experiments. The HMGB2 inhibitor inflachromene and liposome-shHMGB2 (lipo-shHMGB2) were employed for therapeutic intervention.ResultsThe serum HMGB2 levels were also markedly elevated in patients with liver fibrosis and cirrhosis. Deletion of Hmgb2 in Hmgb2-/- mice or inhibition of HMGB2 in mice using a small molecule ICM slowed the progression of CCl4-induced liver fibrosis despite constant HMGB1 expression. In contrast, AAV8-mediated overexpression of Hmgb2 enchanced CCl4-incuded liver fibrosis. Primary hepatic stellate cells (HSCs) isolated from Hmgb2-/- mice showed significantly impaired transdifferentiation and diminished activation of α-SMA, despite a modest induction of HMGB1 protein. RNA-seq analysis revealed the induction of top 45 CCl4-activated genes in multiple signaling pathways including integrin signaling and inflammation. The activation of these genes by CCl4 were abolished in Hmgb2-/- mice or in ICM-treated mice. These included C-X3-C motif chemokine receptor 1 (Cx3cr1) associated with inflammation, cyclin B (Ccnb) associated with cell cycle, DNA topoisomerase 2-alpha (Top2a) associated with intracellular component, and fibrillin (Fbn) and fibromodulin (Fmod) associated with extracellular matrix.ConclusionWe conclude that HMGB2 is indispensable for stellate cell activation. Therefore, HMGB2 may serve as a potential therapeutic target to prevent HSC activation during chronic liver injury. The blood HMGB2 level may also serve as a potential diagnostic marker to detect early stage of liver fibrosis and cirrhosis in humans.
| S-EPMC10629741 | biostudies-literature
Project description:Liver fibrosis represents a common outcome of most chronic liver diseases. Advanced fibrosis leads to cirrhosis for which no effective treatment is available except liver transplantation. Because of the limitations of liver transplantation, alternative therapeutic strategies are an urgent need to find. Recently, mesenchymal stem cells (MSCs) based therapy has been suggested as an attractive therapeutic option for liver fibrosis and cirrhosis, based on the promising results from preclinical and clinical studies. Although the precise mechanisms of MSC transplantation are still not fully understood, accumulating evidence has indicated that MSCs eliminate the progression of fibrosis due to their immune-modulatory properties. In this review, we summarise the properties of MSCs and their clinical application in the treatment of liver fibrosis and cirrhosis. We also discuss the mechanisms involved in MSC-dependent regulation of immune microenvironment in the context of liver fibrosis and cirrhosis.
| S-EPMC7347778 | biostudies-literature
Project description:(1) Background: Liver fibrosis is currently one of the top ten causes of death worldwide. Stem cells transplantation using mesenchymal stem cells (MSCs) is an alternative therapy which is used in the place of organ transplant, due to the incapacity of stem cells to endure oxidative stress in the damage site, thus affecting the healing process. The present study aimed to enhance the therapeutic potential of MSCs using combined therapy, along with the novel synthetic compounds of benzimidazol derivatives. (2) Methods: Eighteen compound series (benzimidazol derivatives) were screened against liver fibrosis using an in vitro CCl4-induced injury model on cultured hepatocytes. IC50 values were calculated on the bases of LDH assay and cell viability assay. (3) Results: Among the eighteen compounds, compounds (10), (14) and (18) were selected on the basis of IC50 value, and compound (10) was the most potent and had the lowest IC50 value in the LDH assay (8.399 ± 0.23 uM) and cell viability assay (4.73 ± 0.37 uM). Next, these compounds were combined with MSCs using an in vitro hepatocytes injury culture and in vivo rat fibrotic model. The effect of the MSCs + compounds treatment on injured hepatocytes was evaluated using LDH assay, cell viability assay, GSH assay and real-time PCR analysis and immuno-staining for caspase-3. Significant reductions in LDH level, caspase-3 and apoptotic marker genes were noted in MSCs + compounds-treated injured hepatocytes. In vivo data also showed the increased homing of the MSCs, along with compounds after transplantation. Real-time PCR analysis and TUNEL assay results also support our study. (4) Conclusions: It was concluded that compounds (10), (14) and (18) can be used in combination with MSCs to reduce liver fibrosis.
| S-EPMC9965641 | biostudies-literature
Project description:BackgroundUmbilical cord mesenchymal stem cells (UCMSCs) have been demonstrated to have good therapeutic effects in the treatment of HBV-related liver diseases. However, the therapeutic effect of UCMSCs on HBV-related liver failure and liver cirrhosis and the variations in the efficacy of UCMSCs after different treatment courses remain poorly understood. Therefore, this study was designed to answer these two questions.MethodsThis was an observational study that retrospectively considered a 3-year period during which 513 patients who received stem cell infusion and met the criteria of hepatic failure and liver cirrhosis were identified from the databases of the Third Affiliated Hospital of Sun Yat-sen University. The eligible patients were categorized into the liver failure group and liver cirrhosis group. The two groups were divided into different subgroups according to the duration of stem cell therapy. In the liver failure group, group A received more than 4 weeks and group B received less than 4 weeks of stem cell therapy. In the liver cirrhosis group, patients who received more than 4 weeks of stem cell therapy belonged to group C, and the patients in group D received less than 4 weeks of stem cell therapy. The patients were followed up for 24 weeks. The demographics, clinical characteristics, biochemical factors, and model for end-stage liver disease (MELD) scores were recorded and compared among different groups.ResultsA total of 64 patients met the criteria for liver failure, and 59 patients met the criteria for liver cirrhosis. After UCMSC treatment, the levels of alanine aminotransferase (ALT), glutamic-oxaloacetic transaminase (AST), and total bilirubin (TBIL) at all postbaseline time points were significantly lower than those at baseline in the liver failure group and liver cirrhosis group; the prothrombin activity (PTA) and MELD scores gradually improved in only the liver failure group. Four weeks after UCMSC treatment, patients who received prolonged treatment with UCMSCs had a larger decrease in TBIL levels than patients who terminated treatment with UCMSCs. After more than 4 weeks of UCMSC treatment, there were no statistically significant differences in the changes in ALT, AST, TBIL, and PTA values and MELD scores between patients with liver failure who received prolonged treatment with UCMSCs and patients with liver cirrhosis who received prolonged treatment with UCMSCs at any time point. However, the median decrease and cumulative decrease in the TBIL level of patients with liver failure with a standard 4-week treatment course were larger than those of patients with liver cirrhosis with a standard 4-week treatment course.ConclusionPeripheral infusion of UCMSCs showed good therapeutic effects for HBV-related liver failure and liver cirrhosis. Prolonging the treatment course can increase the curative effect of UCMSCs for end-stage liver disease, especially for patients with cirrhosis.
| S-EPMC7350639 | biostudies-literature
Project description:BackgroundBone marrow-derived mesenchymal stem cell (BMMSC)-based therapy has become a major focus for treating liver fibrosis/cirrhosis. However, although these cell therapies promote the treatment of this disease, the heterogeneity of BMMSCs, which causes insufficient efficacy during clinical trials, has not been addressed. In this study, we describe a novel Percoll-Plate-Wait procedure (PPWP) for the isolation of an active cell subset from BMMSC cultures that was characterized by the expression of neuroglial antigen 2 (NG2/BMMSCs).MethodsBy using the key method of PPWP and other classical biological techniques we compared NG2/BMMSCs with parental BMMSCs in biological and functional characteristics within a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis injury male C57BL/6 mouse model also in a culture system. Of note, the pathological alterations in the model is quite similar to humans'.ResultsThe NG2/BMMSCs revealed more advantages compared to parentalBMMSCs. They exhibited greater proliferation potential than parental BMMSCs, as indicated by Ki-67 immunofluorescence (IF) staining. Moreover, higher expression of SSEA-3 (a marker specific for embryonic stem cells) was detected in NG2/BMMSCs than in parental BMMSCs, which suggested that the "stemness" of NG2/BMMSCs was greater than that of parental BMMSCs. In vivo studies revealed that an injection of NG2/BMMSCs into mice with ongoing DEN-induced liver fibrotic/cirrhotic injury enhanced repair and functional recovery to a greater extent than in mice treated with parental BMMSCs. These effects were associated with the ability of NG2/BMMSCs to differentiate into bile duct cells (BDCs). In particular, we discovered for the first time that NG2/BMMSCs exhibit unique characteristics that differ from those of parental BMMSCs in terms of producing liver sinusoidal endothelial cells (LSECs) to reconstruct injured blood vessels and sinusoidal structures in the diseased livers, which are important for initiating hepatocyte regeneration. This unique potential may also suggest that NG2/BMMSCs could be an novel off-liver progenitor of LSECs. Ex vivo studies revealed that the NG2/BMMSCs exhibited a similar trend to that of their in vivo in terms of functional differentiation responding to the DEN-diseased injured liver cues. Additionally, the obvious core role of NG2/BMMSCs in supporting the functions of BMMSCs in bile duct repair and BDC-mediated hepatocyte regeneration might also be a novel finding.ConclusionsOverall, the PPWP-isolated NG2/BMMSCs could be a novel effective cell subset with increased purity to serve as a new therapeutic tool for enhancing treatment efficacy of BMMSCs and special seed cell source (BDCs, LSECs) also for bioliver engineering.
| S-EPMC11227708 | biostudies-literature
Project description:Currently, the most effective therapy for liver diseases is liver transplantation, but its use is limited by organ donor shortage, economic reasons, and the requirement for lifelong immunosuppression. Mesenchymal stem cell (MSC) transplantation represents a promising alternative for treating liver pathologies in both human and veterinary medicine. Interestingly, these pathologies appear with a common clinical and pathological profile in the human and canine species; as a consequence, dogs may be a spontaneous model for clinical investigations in humans. The aim of this work was to characterize canine adipose-derived MSCs (cADSCs) and compare them to their human counterpart (hADSCs) in order to support the application of the canine model in cell-based therapy of liver diseases. Both cADSCs and hADSCs were successfully isolated from adipose tissue samples. The two cell populations shared a common fibroblast-like morphology, expression of stemness surface markers, and proliferation rate. When examining multilineage differentiation abilities, cADSCs showed lower adipogenic potential and higher osteogenic differentiation than human cells. Both cell populations retained high viability when kept in PBS at controlled temperature and up to 72 h, indicating the possibility of short-term storage and transportation. In addition, we evaluated the efficacy of autologous ADSCs transplantation in dogs with liver diseases. All animals exhibited significantly improved liver function, as evidenced by lower liver biomarkers levels measured after cells transplantation and evaluation of cytological specimens. These beneficial effects seem to be related to the immunomodulatory properties of stem cells. We therefore believe that such an approach could be a starting point for translating the results to the human clinical practice in future.
| S-EPMC6321531 | biostudies-other
Project description:Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
| S-EPMC9284869 | biostudies-literature
Project description:: Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl4)-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) resulted in fibrotic scar resolution. SHED-CM suppressed the gene expression of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED-CM induced tissue-repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED-CM suppressed the CCl4-induced apoptosis of primary cultured hepatocytes. SHED-CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF-depleted SHED-CM (dHGF-CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED-CM, but not dHGF-CM, inhibited CCl4-induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED-CM-mediated resolution of LF. Taken together, our findings suggest that SHED-CM provides multifaceted therapeutic benefits for the treatment of LF.SignificanceThis study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum-free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED-CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced differentiation of tissue-repairing macrophages expressing high levels of the profibrinolytic factor matrix metalloproteinase 13. Furthermore, hepatocyte growth factor played a central role in the SHED-CM-mediated resolution of LF. This is the first report demonstrating the multifaceted therapeutic benefits of secreted factors derived from SHEDs for LF.
| S-EPMC5031178 | biostudies-literature
Project description:Cirrhosis is the terminal stage of hepatic diseases and is prone to develop into hepatocyte carcinoma. Increasing evidence suggests that the transplantation of dental pulp stem cells (DPSCs) may promote recovery from cirrhosis, but the key regulatory mechanisms involved remain to be determined. In this study, we overexpressed human hepatocyte growth factor (hHGF) in primary rat DPSCs and evaluated the effects of HGF overexpression on the biological behaviors and therapeutic efficacy of grafted DPSCs in cirrhosis. Liver cirrhosis was induced via the intraperitoneal injection of CCl4 twice weekly for 12 weeks and was verified through histopathological and serological assays. HGF was overexpressed in DPSCs via transduction with a hHGF-lentiviral vector and confirmed based on the elevated expression and secretion of HGF. The HGF-overexpressing DPSCs were transplanted into rats intravenously. The HGF-overexpressing DPSCs showed increased survival and hepatogenic differentiation in host liver tissue at 6 weeks after grafting. They also exhibited a significantly greater repair potential in relation to cirrhosis pathology and impaired liver function than did DPSCs expressing HGF at physiological levels. Our study may provide an experimental basis for the development of novel methods for the treatment of liver cirrhosis in clinical practice.
| S-EPMC5693919 | biostudies-literature