scholarly journals Resistin promotes cardiac homing of mesenchymal stem cells and functional recovery after myocardial ischemia-reperfusion via the ERK1/2-MMP-9 pathway

2019 ◽  
Vol 316 (1) ◽  
pp. H233-H244 ◽  
Author(s):  
Yuan He ◽  
Yanjie Guo ◽  
Yunlong Xia ◽  
Yongzhen Guo ◽  
Rutao Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myocardial Ischemia ◽  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion ◽  
Matrix Metalloproteinase 9 ◽  
Myocardial Ischemia Reperfusion ◽  
And Migration ◽  
Metalloproteinase 9 ◽  
Proliferation And Migration

Stem cell therapy is a potentially effective and promising treatment for ischemic heart disease. Resistin, a type of adipokine, has been found to bind to adipose-derived mesenchymal stem cells (ADSCs). However, the effects of resistin on cardiac homing by ADSCs and on ADSC-mediated cardioprotective effects have not been investigated. ADSCs were obtained from enhanced green fluorescent protein transgenic mice. C57BL/6J mice were subjected to myocardial ischemia-reperfusion (I/R) or sham operations. Six hours after the I/R operation, mice were intravenously injected with resistin-treated ADSCs (ADSC-resistin) or vehicle-treated ADSCs (ADSC-vehicle). Cardiac homing by ADSCs and cardiomyocyte apoptosis were investigated 3 days after I/R. Cardiac function, fibrosis, and angiogenesis were evaluated 4 wk after I/R. Cellular and molecular mechanisms were investigated in vitro using cultured ADSCs. Both immunostaining and flow cytometric experiments showed that resistin treatment promoted ADSC myocardial homing 3 days after intravenous injection. Echocardiographic experiments showed that ADSC-resistin, but not ADSC-vehicle, significantly improved left ventricular ejection fraction. ADSC-resistin transplantation significantly mitigated I/R-induced fibrosis and reduced atrial natriuretic peptide/brain natriuretic peptide mRNA expression. In addition, cardiomyocyte apoptosis was reduced, whereas angiogenesis was increased by ADSC-resistin treatment. At the cellular level, resistin promoted ADSC proliferation and migration but did not affect H2O2-induced apoptosis. Molecular experiments identified the ERK1/2-matrix metalloproteinase-9 pathway as a key component mediating the effects of resistin on ADSC proliferation and migration. These results demonstrate that resistin can promote homing of injected ADSCs into damaged heart tissue and stimulate functional recovery, an effect mediated through the ERK1/2 signaling pathway and matrix metalloproteinase-9. NEW & NOTEWORTHY First, intravenous injection of adipose-derived mesenchymal stem cells (ADSCs) treated with resistin significantly increased angiogenesis and reduced myocardial apoptosis and fibrosis in a murine model of ischemia-reperfusion, resulting in improved cardiac performance. Second, resistin treatment significantly increased myocardial homing of intravenously delivered ADSCs. Finally, the ERK1/2-matrix metalloproteinase 9 pathway contributed to the higher proliferative and migratory capacities of ADSCs treated with resistin.

scholarly journals Exosomes Derived from Anoxia Preconditioned Mesenchymal Stem Cells alleviate Myocardial Ischemia Reperfusion Injury by Inhibiting Pyroptosis/ Caspase-1 Induced Apoptosis in The Deficiency of Gasdermin D

2020 ◽  
Author(s):  
Chengyu Mao ◽  
Dongjiu Li ◽  
En Zhou ◽  
Erhe Gao ◽  
Tiantian Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Interacting Protein ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Abstract BackgroundExosomes derived from adipose-derived mesenchymal stem cells can potentially protect cardiomyocytes from myocardial ischemia reperfusion injury. It's notable that exosomes derived from adipose-derived mesenchymal stem cells underwent anoxia preconditioning showed a better cardioprotective effect than that without anoxia. Here, in vitro and in vivo studies were used to investigate the cardioprotective effects against myocardial ischemia reperfusion injury of exosomes derived from adipose-derived mesenchymal stem cells with (Int-EXO) or without anoxia (NC-EXO), respectively. Methods: Adipose-derived mesenchymal stem cells and exosomes were identified by western blot, flow cytometry, transmission electron microscopy, and nanosight. An exosome tracer assay identified exosomes absorbed by cells. An in vitro model using mice cardiomyocytes for studying anoxia-reoxygenation and an in vivo mice model of MIRI were used to investigate the cardioprotective effects of NC-Exo and Int-Exo, respectively.ResultsWe discovered that treatment with NC-EXO and Int-EXO significantly reduced the infarct size and attenuated cardiomyocyte apoptosis, In addition, Int-EXO group had a less infarct size and apoptosis degree. The mechanism revealed by RNA sequencing showed that 40 miRNAs were up-regulated in Int-EXO compared to NC-EXO. 10 of these miRNAs could bind thioredoxin-interacting protein as a downstream target gene; among these, the top-discrepant miRNA224-5p was selected for further study. Dual luciferase reporter assay and rescue study verified TXNIP as a target gene for miR-224-5p. Furthermore, the cellular death signaling pathway which Int-EXO involved in mediating was in a special form of apoptosis, not pyroptosis, induced by activated thioredoxin-interacting protein-pyroptosis-caspase1 pathway in gasdermin D-deficient cells. ConclusionThe research demonstrated adipose-derived mesenchymal stem cells exosomes attenuated MIRI by inhibiting pyroptosis-induced apoptosis in cardiomyocytes which are lack of gasdermin D. The cardioprotective effect of Int-EXO was more significant than that of NC-EXO, possibly due to treated with anoxia preconditioning, adipose-derived mesenchymal stem cells product more miRNAs targeting thioredoxin-interacting protein in exosomes to alleviate pyroptosis-induced apoptosis. These findings provide new insights into the pathogenesis and methods for intervention of myocardial ischemia reperfusion injury.

scholarly journals S100A8/A9 Enhances Immunomodulatory and Tissue-Repairing Properties of Human Amniotic Mesenchymal Stem Cells in Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Vol 22 (20) ◽  
pp. 11175
Author(s):  
Tzu-Jou Chen ◽  
Yen-Ting Yeh ◽  
Fu-Shiang Peng ◽  
Ai-Hsien Li ◽  
Shinn-Chih Wu
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myocardial Ischemia ◽  
Conditioned Medium ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Therapeutic Effects ◽  
Paracrine Factors ◽  
Amniotic Mesenchymal Stem Cells ◽  
Myocardial Ischemia Reperfusion

Paracrine factors of human mesenchymal stem cells (hMSCs) have the potential of preventing adverse cardiac remodeling after myocardial infarction (MI). S100A8 and S100A9 are calcium-binding proteins playing essential roles in the regulation of inflammation and fibrous tissue formation, and they might modulate the paracrine effect of hMSCs. We isolated human amniotic mesenchymal stem cells (hAMSCs) and examined the changes in the expression level of regulatory genes of inflammation and fibrosis after hAMSCs were treated with S100A8/A9. The anti-inflammatory and anti-fibrotic effects of hAMSCs pretreated with S100A8/A9 were shown to be superior to those of hAMSCs without S100A8/A9 pretreatment in the cardiomyocyte hypoxia/reoxygenation experiment. We established a murine myocardial ischemia/reperfusion model to compare the therapeutic effects of the conditioned medium of hAMSCs with or without S100A8/A9 pretreatment. We found the hearts administered with a conditioned medium of hAMSCs with S100A8/A9 pretreatment had better left ventricular systolic function on day 7, 14, and 28 after MI. These results suggest S100A8/A9 enhances the paracrine therapeutic effects of hAMSCs in aspects of anti-inflammation, anti-fibrosis, and cardiac function preservation after MI.

scholarly journals Tanshinone ⅡA Enhances the Therapeutic Efficacy of Mesenchymal Stem Cells Derived Exosomes in Myocardial Ischemia/reperfusion Injury via Up-regulating miR-223-5p

2021 ◽  
Author(s):  
Sheng Li ◽  
Lan Li ◽  
Rui Guo ◽  
Weilong Cao ◽  
Zhihao Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Myocardial Ischemia ◽  
High Throughput Sequencing ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tanshinone Iia ◽  
Intramyocardial Injection ◽  
Myocardial Ischemia Reperfusion

Abstract Background: Myocardial ischemia-reperfusion (I/R) injury is a serious obstacle for patients with coronary heart disease to benefit from post-ischemic reflow. After myocardial I/R injury, CCR2+-resident macrophages are rapidly activated and participate in the subsequent inflammatory response, whereas CCR2--resident macrophages play a major role in attenuating cardiac inflammation and promoting tissue repair. Mesenchymal stem cells (MSCs) have gradually become attractive candidates that aid in understanding the pathogenesis and progression of cardiovascular diseases. The low immunogenicity and low carcinogenicity of stem cell-derived exosomes offer advantage in treating myocardial injuries. In this study, we investigated whether MSC-derived exosomes pretreated with tanshinone IIA (TSA) could exhibit stronger cardioprotective function in an I/R rat model and explored its underlying mechanism. Methods: We investigated the effect of TSA-MSCexo on myocardial I/R injury in vivo. The overexpression of CCR2 in the rat heart was used to determine the regulatory role of CCR2 in I/R injury. High-throughput sequencing of MSCexo and TSA-MSCexo to screen differential genes to explore the mechanism of TSA-MSCexo's cardioprotective effect. Results: Compared with MSCexo, an intramyocardial injection of TSA-MSCexo was found to be more effective in rats in improving cardiac function, limiting the infarct size, inhibiting CCR2 activation, reducing monocyte infiltration and promoting angiogenesis in the heart after myocardial I/R. Moreover, CCR2 had a regulatory effect on monocyte infiltration and angiogenesis after I/R. Bioinformatics analysis and miRNA sequencing of MSCexo and TSA-MSCexo revealed miR-223-5p an effective candidate mediator for TSA-MSCexo to exert its cardioprotective function and CCR2 as the downstream target. Conclusion: In summary, our findings indicated that miR-223-5p packaged in TSA-MSCexo inhibited CCR2 activation to reduce monocyte infiltration and enhanced angiogenesis to alleviate myocardial I/R injury in rats. Thus, the development of an alternative therapy of TSA combined with stem cell-derived exosomes provides an effective strategy for the clinical therapies of ischemic cardiomyopathy.

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