scholarly journals Exosomes from Human-Induced Pluripotent Stem Cell–Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway

2017 ◽  
Vol 43 (2) ◽  
pp. 611-625 ◽  
Author(s):  
Yingdong Du ◽  
Dawei Li ◽  
Conghui Han ◽  
Haoyu Wu ◽  
Longmei Xu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Induced Pluripotent Stem Cell ◽  
Sphingosine Kinase ◽  
Hepatic Ischemia ◽  
Proliferation Markers ◽  
Sphingosine 1 Phosphate ◽  
Induced Pluripotent

Background/Aims: This study aimed to evaluate the effects of exosomes produced by human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic ischemia-reperfusion (I/R) injury, as well as the underlying mechanisms. Methods: Exosomes derived from hiPSC-MSCs were isolated and characterized both biochemically and biophysically. hiPSC-MSCs-Exo were injected systemically into a murine ischemia/reperfusion injury model via the inferior vena cava, and then the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Primary hepatocytes and human hepatocyte cell line HL7702 were used to test whether exosomes could induce hepatocytes proliferation in vitro. In addition, the expression levels of proliferation markers (proliferation cell nuclear antigen, PCNA; Phosphohistone-H3, PHH3) were measured by immunohistochemistry and Western blot. Moreover, SK inhibitor (SKI-II) and S1P1 receptor antagonist (VPC23019) were used to investigate the role of sphingosine kinase and sphingosine-1-phosphate-dependent pathway in the effects of hiPSC-MSCs-Exo on hepatocytes. Results: hiPSCs were efficiently induced into hiPSC-MSCs that had typical MSC characteristics. hiPSC-MSCs-Exo had diameters ranging from 100 to 200 nm and expressed exosome markers (Alix, CD63 and CD81). After hiPSC-MSCs-Exo administration, hepatocyte necrosis and sinusoidal congestion were markedly suppressed in the ischemia/reperfusion injury model, with lower histopathological scores. The levels of hepatocyte injury markers AST and ALT were significantly lower in the treatment group compared to control, and the expression levels of proliferation markers (PCNA and PHH3) were greatly induced after hiPSC-MSCs-Exo administration. Moreover, hiPSC-MSCs-Exo also induced primary hepatocytes and HL7702 cells proliferation in vitro in a dose-dependent manner. We found that hiPSC-MSCs-Exo could directly fuse with target hepatocytes or HL7702 cells and increase the activity of sphingosine kinase and synthesis of sphingosine-1-phosphate (S1P). Furthermore, the inhibition of SK1 or S1P1 receptor completely abolished the protective and proliferative effects of hiPSC-MSCs-Exo on hepatocytes, both in vitro and in vivo. Conclusions: Our results demonstrated that hiPSC-MSCs-Exo could alleviate hepatic I/R injury via activating sphingosine kinase and sphingosine-1-phosphate pathway in hepatocytes and promote cell proliferation. These findings represent a novel mechanism that potentially contributes to liver regeneration and have important implications for new therapeutic approaches to acute liver disease.

scholarly journals Modelling ischemia-reperfusion injury (IRI) in vitro using metabolically matured induced pluripotent stem cell-derived cardiomyocytes

2018 ◽  
Vol 2 (2) ◽  
pp. 026102 ◽  
Author(s):  
Alejandro Hidalgo ◽  
Nick Glass ◽  
Dmitry Ovchinnikov ◽  
Seung-Kwon Yang ◽  
Xinli Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Reperfusion Injury ◽  
Pluripotent Stem Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals N6-methyladenosine demethylase FTO impairs hepatic ischemia–reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ying Dong Du ◽  
Wen Yuan Guo ◽  
Cong Hui Han ◽  
Ying Wang ◽  
Xiao Song Chen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fragmentation ◽  
Hepatic Ischemia ◽  
Adeno Associated Virus ◽  
Downstream Target ◽  
Hepatic Ischemia Reperfusion

AbstractDespite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.

Novel In Vitro Model For Studying Hepatic Ischemia-Reperfusion Injury Using Liver Cubes

2011 ◽  
Vol 165 (2) ◽  
pp. 281-282
Author(s):  
B.J. DuBray ◽  
K.D. Conzen ◽  
G.A. Upadhya ◽  
P. Balachandran ◽  
J. Jia ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
In Vitro Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Vitro Model ◽  
Hepatic Ischemia Reperfusion

scholarly journals MicroRNA-141-3p Attenuates Oxidative Stress-induced Hepatic Ischemia Reperfusion Injury via Keap1/Nrf2 Pathway

2021 ◽  
Author(s):  
Tingting Li ◽  
Qingsong Chen ◽  
Jiangwen Dai ◽  
Zuotian Huang ◽  
Yunhai Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Abstract Hepatic ischemia reperfusion injury (IRI) is a major factor affecting the prognosis of liver transplantation through a series of severe cell death and inflammatory responses. MicroRNA-141-3p (miR-141-3p) has been reported to be associated with hepatic steatosis and other liver diseases. However, the potential role of miR-141-3p in hepatic IRI is currently unknown. In the present study, we found that miR-141-3p levels were negatively correlated with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) in liver transplantation patients. The results demonstrated that miR-141-3p was decreased in mouse liver tissue after hepatic IRI in mice and in hepatocytes after hypoxia/reoxygenation (H/R). Overexpression of miR-141-3p directly decreased Kelch-like ECH-associated protein 1 (Keap1) levels and attenuated cell apoptosis in vivo and in vitro, while inhibition of miR-141-3p facilitated apoptosis. Further experiments revealed that overexpression of miR-141-3p also attenuated oxidative stress-induced damage in hepatocytes under H/R conditions. Taken together, our results indicate that miR-141-3p plays a major role in hepatic IRI through the Keap1 signaling pathway, and the present study suggests that miR-141-3p might have a protective effect on hepatic IRI to some extent.

scholarly journals Polyethylene Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia Reperfusion Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mohamed Bejaoui ◽  
Eirini Pantazi ◽  
Maria Calvo ◽  
Emma Folch-Puy ◽  
Anna Serafín ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Rat Liver ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Water Soluble ◽  
Effective Strategy ◽  
Sprague Dawley ◽  
Hepatic Ischemia

Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proven their effectiveness in variousin vivoandin vitromodels of tissue injury. The present study aims to investigate whether the intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) could be an effective strategy for rat liver preconditioning against IRI. PEG 35 was intravenously administered at 2 and 10 mg/kg to male Sprague Dawley rats. Then, rats were subjected to one hour of partial ischemia (70%) followed by two hours of reperfusion. The results demonstrated that PEG 35 injected intravenously at 10 mg/kg protected efficiently rat liver against the deleterious effects of IRI. This was evidenced by the significant decrease in transaminases levels and the better preservation of mitochondrial membrane polarization. Also, PEG 35 preserved hepatocyte morphology as reflected by an increased F-actin/G-actin ratio and confocal microscopy findings. In addition, PEG 35 protective mechanisms were correlated with the activation of the prosurvival kinase Akt and the cytoprotective factor AMPK and the inhibition of apoptosis. Thus, PEG may become a suitable agent to attempt pharmacological preconditioning against hepatic IRI.

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