Abstract 19213: Epigenetically Reprogrammed Mesenchymal Stem Cells Improve Myocardial Remodeling and Cardiac Function After Myocardial Infarction by Modulating Post-infarct Inflammation and Neoangiogenesis

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jin Jin Kim ◽  
Eun-Hye Park ◽  
Hyo Eun Park ◽  
Eunmin Kim ◽  
Young Choi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Cardiac Function ◽  
M2 Macrophage ◽  
Myocardial Remodeling ◽  
Infarct Zone ◽  
M1 Macrophage

Background: The efficacy of transplantation of default mesenchymal stem cells (MSCs) is controversial because of their limited plasticity and decreased function in elderly patients with myocardial infarction (MI). We investigated whether epigenetically reprogrammed-MSCs ameliorate myocardial remodeling in a mouse model of MI. Methods: Bone marrow-derived MSCs were sequentially treated with 5 mM/L of valproic acid and 100 nM/L of 5-azacytidine for 48 hours. Quantitative RT-PCR was performed to evaluate the effect of epigenetic modifiers on the gene expression of MSCs. 2 x 105 default MSCs, 2 x 105 epigenetically reprogrammed-MSCs, or phosphate-buffered saline were injected into peri-infarct zone immediately after ligating proximal portion of left anterior descending artery. On days 28 after MI, in vivo cardiac magnetic resonance (CMR) and harvest of heart tissue was sequentially performed. Results: Epigenetic modification of MSCs induced gene expression of anti-inflammatory markers such as transforming growth factor-β, indoleamine 2,3-dioxygenase. Fibroblast growth factor-β increased 37.5% and myocyte-specific enhancer factor 2C increased 36.8% at the mRNA level. Transplantation of modified-MSCs showed improved ejection fraction on CMR. In histopathologic analysis, infarct size was significantly decreased in modified-MSCs transplanted mice (p=0.002). When assessing capillary density of peri-infarct zone, larger number of CD31+ staining vascular structures was observed in modified-MSCs transplanted mice. Immunofluorescence stain showed marked increase of CD4+CD25+Foxp3+ regulatory T cells as well as CD68+MR+ M2 macrophage and decrease of CD68+iNOs+ M1 macrophage in modified-MSCs transplanted mice. Conclusions: Transplantation of epigenetically reprogrammed-MSCs significantly improves cardiac function by modulating post-infarct inflammation and neoangiogenesis in a preclinical model of AMI.

scholarly journals MiR-34a inhibitor protects mesenchymal stem cells from hyperglycaemic injury through the activation of the SIRT1/FoxO3a autophagy pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fengyun Zhang ◽  
Fei Gao ◽  
Kun Wang ◽  
Xiaohong Liu ◽  
Zhuoqi Zhang
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Cardiac Function ◽  
Cell Viability ◽  
High Glucose ◽  
Autophagy Pathway ◽  
Precise Role

Abstract Background Mesenchymal stem cells (MSCs) are favourable treatments for ischaemic diseases; however, MSCs from diabetic patients are not useful for this purpose. Recent studies have shown that the expression of miR-34a is significantly increased in patients with hyperglycaemia; the precise role of miR-34a in MSCs in diabetes needs to be clarified. Objective The aim of this study is to determine the precise role of miR-34a in MSCs exposed to hyperglycaemia and in recovery heart function after myocardial infarction (MI) in diabetes mellitus (DM) rats. Methods DM rat models were established by high-fat diet combined with streptozotocin (STZ) injection. MSCs were isolated from the bone marrow of donor rats. Chronic culture of MSCs under high glucose was used to mimic the DM micro-environment. The role of miR-34a in regulating cell viability, senescence and paracrine effects were investigated using a cell counting kit-8 (CCK-8) assay, senescence-associated β-galactosidase (SA-β-gal) staining and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) ELISA, respectively. The expression of autophagy- and senescence-associated proteins in MSCs and silent information regulator 1 (SIRT1) and forkhead box class O 3a (FoxO3a) were analysed by western blotting. Autophagic bodies were analysed by transmission electron microscopy (TEM). The MI model was established by left anterior descending coronary artery (LAD) ligation, and then, the rats were transplanted with differentially treated MSCs intramuscularly at sites around the border zone of the infarcted heart. Thereafter, cardiac function in rats in each group was detected via cardiac ultrasonography at 1 week and 3 weeks after surgery. The infarct size was determined through a 2,3,5-triphenyltetrazolium chloride (TTC) staining assay, while myocardial fibrosis was assessed by Masson staining. Results The results of the current study showed that miR-34a was significantly increased under chronic hyperglycaemia exposure. Overexpression of miR-34a was significantly associated with impaired cell viability, exacerbated senescence and disrupted cell paracrine capacity. Moreover, we found that the mechanism underlying miR-34a-mediated deterioration of MSCs exposed to high glucose involved the activation of the SIRT1/FoxO3a autophagy pathway. Further analysis showed that miR-34a inhibitor-treated MSC transplantation could improve cardiac function and decrease the scar area in DM rats. Conclusions Our study demonstrates for the first time that miR-34a mediates the deterioration of MSCs’ functions under hyperglycaemia. The underlying mechanism may involve the SIRT1/FoxO3a autophagy signalling pathway. Thus, inhibition of miR-34a might have important therapeutic implications in MSC-based therapies for myocardial infarction in DM patients.

scholarly journals MiR-34a inhibitor protects mesenchymal stem cells from hyperglycaemic injury through the activation of the SIRT1/FoxO3a autophagy pathway

2021 ◽  
Author(s):  
Fengyun Zhang ◽  
Fei Gao ◽  
Kun Wang ◽  
Xiaohong Liu ◽  
Zhuoqi Zhang
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Cardiac Function ◽  
Cell Viability ◽  
High Glucose ◽  
Autophagy Pathway ◽  
Precise Role

Abstract Background Mesenchymal stem cells (MSCs) are favourable treatments for ischaemic diseases; however, MSCs from diabetic patients are not useful for this purpose. Recent studies have shown that the expression of miR-34a is significantly increased in patients with hyperglycaemia, the precise role of miR-34a in MSCs in diabetes need to be clarified.Objective The aim of this study is to determine the precise role of miR-34a in MSCs exposed to hyperglycaemia and in recovery heart function after myocardial infarction (MI) in diabetes mellitus (DM) rats. Methods DM rats models were established by high-fat diet combined with streptozotocin (STZ) injection. MSCs were isolated from the bone marrow of donor rats. Chronic culture of MSCs under high glucose was used to mimic the DM micro-environment. The role of miR-34a in regulating cell viability, senescence and paracrine effects were investigated using a cell counting kit-8 (CCK-8) assay, senescence-associated β-galactosidase (SA-β-gal) staining, and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) ELISA, respectively. The expression of autophagy- and senescence-associated proteins in MSCs and silent information regulator 1 (SIRT1) and forkhead box class O 3a (FoxO3a) were analyzed by western blotting. Autophagic bodies were analyzed by transmission electron microscopy (TEM). The MI model was established by left anterior descending coronary artery (LAD) ligation, and then the rats were transplanted with differentially treated MSCs intramuscularly at sites around the border zone of the infarcted heart. Thereafter, cardiac function in rats in each group was detected via cardiac ultrasonography at 1 week and 3 weeks after surgery. The infarct size was determined through a 2,3,5-triphenyltetrazolium chloride (TTC) staining assay, while myocardial fibrosis was assessed by Masson staining.Results The results of the current study showed that miR-34a was significantly increased under chronic hyperglycaemia exposure. Overexpression of miR-34a was significantly associated with impaired cell viability, exacerbated senescence and disrupted cell paracrine capacity. Moreover, we found that the mechanism underlying miR-34a-mediated deterioration of MSCs exposed to high glucose involved the activation of the SIRT1/FoxO3a autophagy pathway. Further analysis showed that miR-34a inhibitor-treated MSCs transplantation could improve cardiac function and decrease the scar area in DM rats. Conclusions Our study demonstrates for the first time that miR-34a mediates the deterioration of MSCs functions under hyperglycaemia. The underlying mechanism may involve the SIRT1/FoxO3a autophagy signaling pathway. Thus, inhibition of miR-34a might have important therapeutic implications in MSCs-based therapies for myocardial infarction in DM patients.

Mesenchymal Stem Cells Enhanced Cardiac Nerve Sprouting via Nerve Growth Factor in a Rat Model of Myocardial Infarction

2014 ◽  
Vol 20 (12) ◽  
pp. 2023-2029 ◽  
Author(s):  
Jian Chen ◽  
Shaoxin Zheng ◽  
Hui Huang ◽  
Suihua Huang ◽  
Changqing Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Rat Model ◽  
Nerve Growth ◽  
Cardiac Nerve ◽  
Nerve Sprouting

scholarly journals Mesenchymal stem cells with overexpression of Angiotensin-converting enzyme-2 improved the microenvironment and cardiac function in a rat model of myocardial infarction

2020 ◽  
Author(s):  
Chao Liu ◽  
Yue Fan ◽  
Hong-Yi Zhu ◽  
Lu zhou ◽  
Yu Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Angiotensin Converting Enzyme ◽  
Cardiac Function ◽  
Heart Function ◽  
Tube Formation ◽  
Border Zone ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

AbstractBackgroundAngiotensin-converting enzyme-2 (ACE2) overexpression improves left ventricular remodeling and function in diabetic cardiomyopathy; however, the effect of ACE2-overexpressed mesenchymal stem cells (MSCs) on myocardial infarction (MI) remains unexplored. This study aimed to investigate the effect of ACE2-overexpression on the function of MSCs and the therapeutic efficacy of MSCs for MI.MethodsMSCs were transfected with Ace2 gene using lentivirus, and then transplanted into the border zone of ischemic heart. The renin-angiotensin system (RAS) expression, nitric oxide synthase (NOS) expression, paracrine factors, anti-hypoxia ability, tube formation of MSCs, and heart function were determined.ResultsMSCs expressed little ACE2. ACE2-overexpression decreased the expression of AT1 and VEGF apparently, up-regulated the paracrine of HGF, and increased the synthesis of Angiotensin 1-7 in vitro. ACE2-overexpressed MSCs showed a cytoprotective effect on cardiomyocyte, and an interesting tube formation ability, decreased the heart fibrosis and infarct size, and improved the heart function.ConclusionTherapies employing MSCs with ACE2 overexpression may represent an effective treatment for improving the myocardium microenvironment and the cardiac function after MI.

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