Therapeutic potentials of umbilical cord–derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation

Zhang, Yingcai; Liu, Wei; Fu, Binsheng; Wang, Guoying; Li, Haibo; Yi, Huimin; Jiang, Nan; Wang, Genshu; Zhang, Jian; Yi, Shuhong; Li, Hua; Zhang, Qi; Yang, Yang; Chen, Guihua

doi:10.1016/j.jcyt.2016.11.005

Cited by 62 publications

(50 citation statements)

References 32 publications

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“…Although conventional antioxidants have beneficial roles in improving liver I/R injury, these reagents are not convenient for clinical application, largely because their effects and side effects are not fully understood 40 . UC-MSCs are considered as a promising therapeutic tool for several liver diseases [41][42][43][44][45] . This study also confirmed that UC-MSCs protected both liver tissue and L02 hepatocytes against I/R and H/R injury, as demonstrated by decrease of serum liver enzymes, alleviation of liver injury and reduced inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

Zheng

Chen

et al. 2020

Cell Death Dis

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Hepatocyte apoptosis is the main pathophysiological process underlying liver ischemia/reperfusion (I/R) injury. Mitochondrial abnormalities have a vital role in hepatocellular damage. The hepatoprotective effects of mesenchymal stem cells (MSCs) have been previously demonstrated. In this study, we aim to investigate the effect and potential mechanism of MSCs against liver I/R injury. Effects of MSCs were studied in mice liver I/R injury model and in a hypoxia/reoxygenation (H/R) model of L02 hepatocytes. The potential mechanisms of MSCs on these in vivo and in vitro I/R-induced hepatocellular apoptosis models were studies. Accompanied by the improvement of hepatic damage, MSCs exhibited capabilities of controlling mitochondrial quality, shown by reduced mitochondrial reactive oxygen species (mtROS) overproduction, decreased the accumulation of mitochondrial fragmentation, restored ATP generation and upregulated mitophagy. Furthermore, we descripted a potential mechanism of MSCs on upregulating mitophagy and found that the reduced Parkin and PINK1 expression and inactivated AMPKα pathway were observed in the liver tissue in I/R model. These effects were reversed by MSCs treatment. In vitro study showed that MSCconditioned medium (MSC-CM) suppressed hepatocellular apoptosis and inhibited mtROS accumulation in the H/R environment. And these effects of MSC-CM were partially blocked after the cells were transfected with PINK1 siRNA or added with dorsomorphin. Collectively, our findings provide a novel pharmacological mechanism that MSCs exert hepatoprotective effect in liver I/R injury via upregulating PINK1-dependent mitophagy. In addition, this effect might be attributed to the modulation of AMPKα activation.

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Section: Discussionmentioning

confidence: 99%

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

Zheng

Chen

et al. 2020

Cell Death Dis

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“…Patients receiving more than 4 UCMSC transfusions received them at 1, 2, 3, 4, 5, 6, 7 and 8 weeks after recruitment. As reported in previous research (ClinicalTrials.gov, NCT02223897) (14), approximately 1.0 × 10 6 UCMSCs per kilogram of body weight suspended in 100 mL of normal saline solution were infused intravenously through a vein in the forearm for each treatment. The patients were discharged after one day of observation without any adverse events.…”

Section: Ucmsc Preparation and Transfusionmentioning

confidence: 99%

Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis

Jia

Shu

Yang

et al. 2020

Preprint

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Background: This study aimed to investigate the therapeutic effect of umbilical cord mesenchymal stem cells (UCMSCs) on HBV-related liver failure and liver cirrhosis and to compare the different efficacies of UCMSCs after different treatment courses. Methods: This was an observational study that retrospectively considered a three-year period during which 513 patients who received stem cell infusion met the criteria of hepatic failure and liver cirrhosis were identified from databases of the Third Affiliated Hospital of Sun Yat-sen University. Eligible patients were categorized into the liver failure group and liver cirrhosis group. The two groups were divided into different subgroups according to the times of stem cell therapy. In the liver failure group, group A received more than 4 weeks and group B received less than 4 weeks. In the liver cirrhosis group, patients who received more than 4 weeks of stem cell therapy belonged to group C, and group D received less than 4 weeks. The patients were followed up for 24 weeks. The demographics, clinical characteristics, biochemical factors, and MELD scores were recorded and compared among different groups. Results: A total of 64 patients met the criteria of liver failure, and 59 patients met the criteria of liver cirrhosis. After UCMSC treatments, the levels of ALT, AST, and TBIL at all postbaseline time points were significantly lower than those at baseline in the liver failure group and liver cirrhosis group; the PTA and MELD scores only gradually improved in the liver failure group. Four weeks after UCMSC treatment, patients with prolonged treatment with UCMSCs had higher TBIL decline levels than patients who terminated treatment with UCMSCs. After more than 4 weeks of UCMSC treatment, there was no statistically significant difference in the levels of change for ALT, AST, TBIL, PTA value and the MELD score between patients with liver failure with prolonged treatment with UCMSCs and patients with liver cirrhosis with prolonged treatment with UCMSCs at all observation weeks. However, the median decline and cumulative decline in the TBIL level of patients with liver failure with a standard 4-week treatment course were higher than those of patients with liver cirrhosis with a standard 4-week treatment course. Conclusion: Peripheral 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.

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“…In general, MSC administration in patients with different liver pathologies proved to be feasible and safe (Table 1 ). Regarding their efficacy, studies demonstrated that MSCs exert positive effects on liver function by increase in serum levels of albumin and improving coagulation or decreasing bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (γ-GT)[ 17 - 19 , 21 - 24 , 26 , 29 , 31 , 33 - 35 ]. In addition, the MELD (Model for End-stage Liver Disease) and Child-Pugh scores were improved after MSC treatment[ 14 - 19 , 23 , 28 - 32 , 34 ] (Table 1 ).…”

Section: Clinical Trials Involving the Use Of Mscs In Liver Diseasesmentioning

confidence: 99%

“…However, no difference was observed in peripheral blood CD4 + T cell proportion and immunosuppression could not be withdrawn in MSC-treated patients. In addition, the administration of umbilical cord-derived MSCs as therapy to prolong graft-survival in patients with severe ischemic-type biliary lesions after liver transplantation was also evaluated[ 24 ]. Six doses of MSCs were infused intravenously every 2-4 wk, and patients were followed-up for 2 years and compared with a prospective cohort of patients treated with standard therapy.…”

Section: Clinical Trials Involving the Use Of Mscs In Liver Diseasesmentioning

confidence: 99%

“…Six doses of MSCs were infused intravenously every 2-4 wk, and patients were followed-up for 2 years and compared with a prospective cohort of patients treated with standard therapy. Remarkably, MSCs were safe, improved hepatic function, prolonged graft-survival and did not induce cancer or increase microbial infection events[ 24 ]. In conclusion, these results demonstrated that MSC therapy is a safe procedure, especially in the field of solid organ transplant where intense and prolonged immunosuppression is required.…”

Section: Clinical Trials Involving the Use Of Mscs In Liver Diseasesmentioning

confidence: 99%

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Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

Fiore

Domínguez

Bayo

et al. 2018

WJG

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Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells (MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise, it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles (EVs). EVs contain proteins, lipids and nucleic acids (DNA, mRNA, miRNA, lncRNA) from the cell of origin, allowing for intercellular communication. Recently, different studies have demonstrated that MSC-derived EVs could reproduce, at least in part, the biological effects obtained by MSC-based therapies. Moreover, due to EVs’ stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration, the role of EVs in liver physiopathology and the potential of MSCderived EVs as intercellular mediators and therapeutic tools in liver diseases.

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Therapeutic potentials of umbilical cord–derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation

Cited by 62 publications

References 32 publications

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis

Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

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