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.

scholarly journals Dodging COVID-19 infection: Low expression and localization of Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) in Mesenchymal Stem Cells derived from human umbilical cord (hUC-MSCs). 

2020 ◽  
Author(s):  
Jonathan J Hernandez ◽  
Doyle E Beaty ◽  
Logan L Fruhwirth ◽  
J M Sloan ◽  
Ana P Lopez Chaves ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Mesenchymal Stem Cells ◽  
Angiotensin Converting Enzyme ◽  
Western Blot ◽  
Human Umbilical Cord ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Transmembrane Serine Protease ◽  
Low Expression

Abstract Mesenchymal stem cells derived from human umbilical cord (hUC-MSCs) have immunomodulatory properties that are of interest to treat novel coronavirus disease 2019 (COVID-19). Leng et al. recently reported that hUC-MSCs derived from one donor negatively expressed Angiotensin-Converting Enzyme 2 (ACE2), a key protein for viral infection along with Transmembrane Serine Protease 2 (TMPRSS2). In this report, the expression of ACE2 and TMPRSS2 was analyzed in 24 lots of hUC-MSCs derived from 24 different donors via quantitative polymerase chain reaction (qPCR), Western Blot, immunofluorescence and flow cytometry. hUC-MSCs had significantly lower ACE2 (p=0.002) and TMPRSS2 (p=0.008) expression compared with human lung tissue homogenates in Western blot analyses. Little to no expression of ACE2 or TMPRSS2 was observed in hUC-MSC by qPCR, and they were not observable with immunofluorescence in hUC-MSCs cell membranes. A double negative ACE2 and TMPRSS2 population percentage of 94.30% ±15.55 was obtained for hUC-MSCs via flow cytometry, with only 0.011% ACE2 and 10.91% TMPRSS2 observable positive populations. We have demonstrated negative expression of ACE2 and low expression of TMPRSS2 in 24 lots of hUC-MSCs. This has crucial implications for the design of future therapeutic options for COVID-19, since hUC-MSCs would have the ability to “dodge” viral infection to exert their immunomodulatory effects.

Abstract TP102: Human Placental Mesenchymal Stem Cells Derived Exosome-Angiotensin Converting Enzyme-2 Dependent Protection in Ischemic Stroke Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Mansoureh Barzegar ◽  
Yuping Wang ◽  
Jungmi W. Yun ◽  
Oleg Chernyshev ◽  
Roger Kelley ◽  
...  
Keyword(s):  
Stem Cells ◽  
Blood Flow ◽  
Mesenchymal Stem Cells ◽  
Ischemic Stroke ◽  
Angiotensin Converting Enzyme ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Placental Mesenchymal Stem Cells

Following thrombolytic therapy for stroke, ischemia/reperfusion (I/R) mediated inflammation often disrupts the blood brain barrier (BBB). This can enhance expression of endothelial adhesion markers and perturb normal blood flow regulation. Proposed benefits of stem cell therapy (SCT) in stroke, besides long-term trans-differentiation into neural cells, include secretion of protective factors, which partly depends on exosomes released by stem cells. We evaluated human placenta mesenchymal stem cells (hPMSC) as potential ameliorative SCT in an acute ischemic stroke model. We hypothesize that hPMSC would achieve site-specific suppression of post-ischemic immune cell transmigration, preservation of the BBB and maintenance of blood flow via ‘paracrine’ signaling pathways in acute stroke injury.We found that intraperitoneal (IP) administration of hPMSC at the time of reperfusion, using the middle cerebral artery occlusion (MCAO)/reperfusion model, produced significant protection ( p =0.0001) of the ipsilateral hemisphere. We also demonstrated that hPMSC-treated MCAO mice exhibited significantly greater neurological recovery ( p <0.0001) compared to untreated MCAO, an effect which was accompanied by significant restoration of blood flow ( p <0.01) to the MCAO-stressed brains. Using Evans Blue dye assay, we also observed significant ( p =0.004) improvement of BBB integrity in ipsilateral hemispheres of hPMSC-treated mice vs MCAO controls. Furthermore, we determined that hPMSC-derived exosomes contribute to paracrine based protection of hPMSC in MCAO model. Importantly, we found that hPMSC/exosome protection is mediated partly by the function of angiotensin converting enzyme 2 (ACE2). To evaluate the contribution of ACE2 in protection of the brain after ischemic stroke, we first demonstrated that hPMSC and their exosomes express ACE2. Second, mice injected with hPMSC which had been pre-treated with the specific ACE2 inhibitor (10μM) MLN-4760, showed tissue injury and neurological behavior similar to that seen in untreated MCAO.We conclude that pleiotropic factors associated with hPMSC administration can have a favorable impact on blood flow, BBB integrity potentially alleviating the detrimental effects of ischemic stroke.

scholarly journals Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Peisen Huang ◽  
Li Wang ◽  
Qing Li ◽  
Jun Xu ◽  
Junyan Xu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Cardiac Function ◽  
Inflammatory Responses ◽  
Heart Function ◽  
Border Zone ◽  
Inflammatory Factor ◽  
Intramyocardial Injection

Abstract Background Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs. Methods Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay. Results We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo. Conclusions Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.

scholarly journals The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yueqiu Chen ◽  
Jianfeng Zuo ◽  
Weiqian Chen ◽  
Ziying Yang ◽  
Yanxia Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Heart Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Therapeutic Effects ◽  
Ventricular Ejection Fraction

Abstract Background Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats. Methods and results First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats. Conclusion These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections. Graphical Abstract IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.

scholarly journals MiR-34a Protects Mesenchymal Stem Cells From Hyperglycaemic Injury Through The Activation of The Sirt1/FoxO3a Autophagy Pathway

2020 ◽  
Author(s):  
Fengyun Zhang ◽  
Fei Gao ◽  
Kun Wang ◽  
Xiaohong Liu ◽  
Zhuoqi Zhang
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Cell Viability ◽  
High Glucose ◽  
Border Zone ◽  
Autophagy Pathway ◽  
Precise Role

Abstract BackgroundAutologous 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.ObjectiveThe aim of this study is to determine the precise role of miR-34a in MSCs exposed to hyperglycaemia and in healing the heart after myocardial infarction in diabetes mellitus (DM) rats.MethodsDM rats were established by 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 microenvironment. 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 VEGF and 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 mice were transplanted with differentially treated MSCs intramuscularly at sites around the border zone of the infarcted heart. Thereafter, cardiac function in mice 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.ResultsThe results of the current study showed that miR-34a was significantly upregulated 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 involves 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.ConclusionsOur study demonstrates for the first time that miR-34a mediates the deterioration of MSC 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.

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