scholarly journals FGF21 Mediates Mesenchymal Stem Cell Senescence via Regulation of Mitochondrial Dynamics

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Li ◽  
Yimei Hong ◽  
Haiwei He ◽  
Guojun Jiang ◽  
Wei You ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Signaling Pathway ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Fibroblast Growth Factor 21 ◽  
Early Passage ◽  
Ampk Signaling ◽  
Novel Strategy

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.

scholarly journals Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lixiang Wang ◽  
Xin Li ◽  
Yuki Hanada ◽  
Nao Hasuzawa ◽  
Yoshinori Moriyama ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Er Stress ◽  
Disease Progression ◽  
Acute Liver Injury ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Related Protein ◽  
Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway

2019 ◽  
Author(s):  
Zhou Zhilai ◽  
Tian Xiaobo ◽  
Mo Biling ◽  
Xu Huali ◽  
Yao Shun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Therapeutic Effects ◽  
Mesenchymal Stem Cell Transplantation ◽  
Cord Injury

Abstract Background The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression.Methods Using a mouse model of compression SCI, ADSCs and Jagged1 small interfering RNA (siRNA) were injected into the spinal cord. Locomotor function, spinal cord tissue morphology and the levels of various proteins and transcripts were compared between groups.Results ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium binding adapter molecule 1 (Iba1) and ED1 staining in the injured spinal cord, promoting the survival of neurons. These changes were accompanied by improved functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in a decrease in SCI-induced proinflammatory cytokines as well as the activation of microglia. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 following SCI.Conclusion The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation.

scholarly journals T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Junhua Yang ◽  
Wenbo Guo ◽  
Jianhua Wang ◽  
Xianli Yang ◽  
Zhiqi Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Human Liver ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Mitochondrial Dynamic ◽  
Normal Human Liver ◽  
Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury

2019 ◽  
Vol 133 (3) ◽  
pp. 497-513 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Time Points

Abstract An uncontrolled balance of mitochondrial dynamics has been shown to contribute to cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although inhibition of mitochondrial fission could ameliorate cardiac dysfunction, modulation of mitochondrial fusion by giving a fusion promoter at different time-points during cardiac I/R injury has never been investigated. We hypothesized that giving of a mitochondrial fusion promoter at different time-points exerts cardioprotection with different levels of efficacy in rats with cardiac I/R injury. Forty male Wistar rats were subjected to a 30-min ischemia by coronary occlusion, followed by a 120-min reperfusion. The rats were then randomly divided into control and three treated groups: pre-ischemia, during-ischemia, and onset of reperfusion. A pharmacological mitochondrial fusion promoter-M1 (2 mg/kg) was used for intervention. Reduced mitochondrial fusion protein was observed after cardiac I/R injury. M1 administered prior to ischemia exerted the highest level of cardioprotection by improving both cardiac mitochondrial function and dynamics regulation, attenuating incidence of arrhythmia, reducing infarct size and cardiac apoptosis, which led to the preservation of cardiac function and decreased mortality. M1 given during ischemia and on the onset of reperfusion also exerted cardioprotection, but with a lower efficacy than when given at the pre-ischemia time-point. Attenuating a reduction in mitochondrial fusion proteins during myocardial ischemia and at the onset of reperfusion exerted cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, thus reducing infarct size and improving cardiac function. These findings indicate that it could be a promising intervention with the potential to afford cardioprotection in the clinical setting of acute myocardial infarction.

scholarly journals Mesenchymal Stem Cell Therapy Alleviates Interstitial Cystitis by Activating Wnt Signaling Pathway

2015 ◽  
Vol 24 (14) ◽  
pp. 1648-1657 ◽  
Author(s):  
Miho Song ◽  
Jisun Lim ◽  
Hwan Yeul Yu ◽  
Junsoo Park ◽  
Ji-Youn Chun ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Therapy ◽  
Wnt Signaling ◽  
Interstitial Cystitis ◽  
Signaling Pathway ◽  
Stem Cell Therapy ◽  
Wnt Signaling Pathway ◽  
Mesenchymal Stem Cell Therapy
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