Abstract 16596: Immune Evasion by Human Neonatal Cardiac Mesenchymal Stem Cells Demonstrates Therapeutic Application in Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muthukumar Gunasekaran ◽  
Rachana Mishra ◽  
Progyaparamita Saha ◽  
Aakash Shah ◽  
Lauren Davidson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Cell Retention ◽  
Over Expression ◽  
And Function

Immune rejection of transplanted stem cells is a major stumbling block in designing effective therapy for myocardial infarction. Human neonatal cardiac mesenchymal stem cells (nMSCs) showed superior cardiac functional recovery compared to adult MSCs in immune competent rat MI model. However, molecular mechanisms underlying immune evasion by transplanted nMSCs in the infarcted myocardium remain unexplored. In this investigation, we demonstrate for the first-time the expression, regulation and function of CD47 in human nMSCs and its novel mechanism of immune evasion increases its regenerative potential in rat MI model. Transplanted nMSCs showed significant increased cell retention, reduced phagocytosis and CD68 + cells compared to aMSCs in rat MI model. Comparative proteomic analysis by LC-MS/MS on nMSCs and aMSCs showed that CD47 higher in nMSCs. Increased CD47 expression in nMSCs inhibited phagocytosis compared to aMSCs in vitro and in vivo . Further, CD47 blockade in nMSCs using anti-CD47, siRNA and shRNA lentiviral based approaches increased in vitro , in vivo phagocytosis, CD68 + cells and reduced cell retention and MI recovery in vivo . Microarray analysis and validation showed miR-34a was significantly higher in aMSCs than nMSCs. To unravel CD47 regulation in aMSCs, we performed target scan analysis that predicted miR-34a binds on CD47. Further, miR-34a over expression in nMSCs reduced CD47 expression, increased in vitro and in vivo phagocytosis and reduced cell retention and MI recovery. In conclusion, increased CD47 expression in nMSCs inhibit phagocytosis by CD47/SIRPα immune regulatory axis to demonstrates its immune evasion potential and its therapeutic applications in myocardial infarction.

scholarly journals Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
HuiYa Li ◽  
DanQing Hu ◽  
Guilin Chen ◽  
DeDong Zheng ◽  
ShuMei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Paracrine Factors ◽  
Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

scholarly journals Macrophage-derived Apoptotic Vesicles Regulate Fate Commitment of Mesenchymal Stem Cells via miR155

2021 ◽  
Author(s):  
Yuan Zhu ◽  
Xiao Zhang ◽  
Kunkun Yang ◽  
Yuzi Shao ◽  
Ranli Gu ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Proliferation Ability ◽  
Immunomodulatory Function

Abstract Background In tissue engineering, mesenchymal stem cells (MSCs) are common seed cells because of abundant sources, strong proliferation ability and immunomodulatory function. Numerous researches have demonstrated that MSC-macrophage crosstalk played a key role in the tissue engineering. Macrophages could regulate the differentiation of MSCs via different molecular mechanisms, including extracellular vesicles. Apoptotic macrophages could generate large amounts of apoptotic vesicles (apoVs), whereas the functions of macrophage-derived apoVs remain largely unknown. There was no research to clarify the role of macrophage-derived apoVs in MSC fate choices. In this study, we aimed to characterize macrophage-derived apoVs, and investigate the roles of macrophage-derived apoVs in the fate commitment of MSCs. Methods We characterized macrophage-derived apoVs, and investigated their role in MSC osteogenesis and adipogenesis in vitro and in vivo. Furthermore, we performed microRNA loss- and gain- of function experiments and western blot to determine the molecular mechanism. Results We found that macrophage-derived apoVs inhibited osteogenesis and promoted adipogenesis in vitro and in vivo. In mechanism, apoVs regulated osteogenesis and adipogenesis of MSCs by delivering microRNA155 (miR155). Conclusions Macrophage-derived apoVs could regulate the osteogenesis and adipogenesis of MSCs through delivering miR155, which provided novel insights for MSC-mediated tissue engineering.

scholarly journals Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Kai Kang ◽  
Ruilian Ma ◽  
Wenfeng Cai ◽  
Wei Huang ◽  
Christian Paul ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Infarct Size ◽  
Functional Restoration ◽  
Akt Inhibitor ◽  
Cardiac Functions

Background and Objective.Exosomes secreted from mesenchymal stem cells (MSC) have demonstrated cardioprotective effects. This study examined the role of exosomes derived from MSC overexpressing CXCR4 for recovery of cardiac functions after myocardial infarction (MI).Methods. In vitro, exosomes from MSC transduced with lentiviral CXCR4 (ExoCR4) encoding a silencing sequence or null vector were isolated and characterized by transmission electron microscopy and dynamic light scattering. Gene expression was then analyzed by qPCR and Western blotting. Cytoprotective effects on cardiomyocytes were evaluated and effects of exosomes on angiogenesis analyzed.In vivo, an exosome-pretreated MSC-sheet was implanted into a region of scarred myocardium in a rat MI model. Angiogenesis, infarct size, and cardiac functions were then analyzed.Results. In vitro, ExoCR4significantly upregulatedIGF-1αand pAkt levels and downregulated active caspase 3 levelin cardiomyocytes. ExoCR4also enhanced VEGF expression and vessel formation. However, effects of ExoCR4were abolished by an Akt inhibitor or CXCR4 knockdown.In vivo, ExoCR4treated MSC-sheet implantation promoted cardiac functional restoration by increasing angiogenesis, reducing infarct size, and improving cardiac remodeling.Conclusions.This study reveals a novel role of exosomes derived from MSCCR4and highlights a new mechanism of intercellular mediation of stem cells for MI treatment.

scholarly journals Immunotolerant Properties of Mesenchymal Stem Cells: Updated Review

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Whitney Faiella ◽  
Rony Atoui
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Therapeutic Option ◽  
Clinical Use ◽  
Healthy Donors

Stem cell transplantation is a potential therapeutic option to regenerate damaged myocardium and restore function after infarct. Current research is focused on the use of allogeneic mesenchymal stem cells (MSCs) due to their unique immunomodulatory characteristics and ability to be harvested from young and healthy donors. Both animal and human studies support the immunoprivileged state of MSCs and even demonstrate improvements in cardiac function after transplantation. This research continues to be a topic of interest, as advances will ultimately enable the clinical use of these universal cells for therapy after a myocardial infarction. Updatedin vitro,in vivo, and clinical trial studies are discussed in detail in the following review.

scholarly journals Adipose-Derived Mesenchymal Stem Cells-Derived Exosomes Carry MicroRNA-671 to Alleviate Myocardial Infarction Through Inactivating the TGFBR2/Smad2 Axis

Inflammation ◽  
2021 ◽  
Author(s):  
Xue Wang ◽  
Yuhai Zhu ◽  
Chengcheng Wu ◽  
Wennan Liu ◽  
Yujie He ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Glucose Deprivation ◽  
Bioinformatic Analysis ◽  
In Cells

Abstract Mesenchymal stem cells (MSCs) and their derived extracellular vesicles have been reported as promising tools for the management of heart disease. The aim of this study was to explore the function of adipose-derived MSCs (adMSCs)-derived exosomes (Exo) in the progression of myocardial infarction (MI) and the molecules involved. Mouse cardiomyocytes were treated with oxygen-glucose deprivation (OGD) to mimic an MI condition in vitro. The adMSCs-derived Exo were identified and administrated into the OGD-treated cardiomyocytes, and then the viability and apoptosis of cells, and the secretion of fibrosis- and inflammation-related cytokines in cells were determined. Differentially expressed microRNAs (miRNAs) in cells after Exo treatment were screened using a microarray analysis. The downstream molecules regulated by miR-671 were explored through bioinformatic analysis. Involvements of miR-671 and transforming growth factor beta receptor 2 (TGFBR2) in the exosome-mediated events were confirmed by rescue experiments. A murine model with MI was induced and treated with Exo for functional experiments in vivo. Compared to phosphate-buffered saline treatment, the Exo treatment significantly enhanced viability while reduced apoptosis of cardiomyocytes, and in reduced myocardial fibrosis and inflammation both in vitro and in vivo. miR-671 was significantly upregulated in cells after Exo treatment. Downregulation of miR-671 blocked the protective functions of Exo. miR-671 targeted TGFBR2 and suppressed phosphorylation of Smad2. Artificial downregulation of TGFBR2 enhanced viability of the OGD-treated cardiomyocytes. This study suggested that adMSC-derived exosomal miR-671 directly targets TGFBR2 and reduces Smad2 phosphorylation to alleviate MI-like symptoms both in vivo and in vitro.

scholarly journals Erythropoietin  supports the growth and function of Sca-1+ stem cells and promotes myocardial infarction repair in mice

2020 ◽  
Author(s):  
Lin Zuo ◽  
Duan-duan Li ◽  
Xiu-Xia Ma ◽  
Shan-Hui Shi ◽  
Ding-Chao Lü ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Border Zone ◽  
Adult Mice ◽  
P38mapk Signaling ◽  
And Performance ◽  
Long Acting ◽  
And Function

Abstract Background：Myocardial infarction (MI) is the leading cause of death in the world-wide population. With the improvement of clinical therapy, the mortality in acute MI cases has been significantly reduced. This study was to demonstrate that erythropoietin (EPO) is an effective supporter for Sca-1+ stem cells (SCs) and can promote the repair of myocardial infarction (MI) partially via way of enhancing Sca-1+ SCs activities. Methods: Darbepoetin alpha (a long-acting EPO analog, EPOanlg) (30 mg/kg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocytes apoptosis and regenerations and microvessels density were measured. Lin− Sca-1+ SCs were isolated from neonatal and adult mice hearts and were respectively used to identify the colony forming ability and the supporting effect of EPO on these Sca-1+ SCs. Results: Compared to MI alone, EPOanlg reduced the infarct percentage and cardiomyocyte apoptosis ratio and LV chamber dilatation, improved cardiac performance, increased the regenerated cardiomyocyte ratio in the border zone and the numbers of coronary microvessels, while without obvious adverse effects in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin- Sca-1+ SCs likely via the EPO receptor and Stat5-p38MAPK signaling. Conclusions: EPO promotes Sca-1+ SCs activities and MI repair. The study enlightens the prospects of Sca-1+ SC supporters in the treatment of MI.

scholarly journals Over-expression of PPAR-γ2 gene enhances the adipogenic differentiation of hemangioma-derived mesenchymal stem cells in vitro and in vivo

Oncotarget ◽  
2017 ◽  
Vol 8 (70) ◽  
pp. 115817-115828 ◽  
Author(s):  
Si-Ming Yuan ◽  
Yao Guo ◽  
Qian Wang ◽  
Yuan Xu ◽  
Min Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipogenic Differentiation ◽  
Over Expression ◽  
Γ2 Gene

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

2020 ◽  
Author(s):  
Qiong Li ◽  
Huifang Hou ◽  
Meng Li ◽  
Xia Yu ◽  
Hongbo Zuo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myocardial Injury ◽  
Color Doppler ◽  
Sham Operation ◽  
Sham Operation Group ◽  
Vascular Regeneration

Abstract Background: Cardiovascular disease is the leading cause of death in developed and developing countries. The lack of effective regenerative therapies in the treatment of ischemia‐related diseases requires new therapies to improve clinical outcomes. Thus, MSCs have become a focus in stem cell treatment of myocardial injury. At present, most studies use mixed MSCs in vivo and in vitro. A promising therapeutic strategy for myocardial injury should be using the dominant subgroup with essential biological characteristics. The aim of this study was to utilize the dominant CD73 + subgroup of adipose derived mesenchymal stem cells (ADMSCs) for the therapy of myocardial infarction (MI). Methods: Adult mix gender SD rats, with a body weight of 230±18g, were randomly divided into sham operation group (SHAM), MI group (MI), mixed ADMSCs transplantation group (MI+ADMSCs), CD73 + ADMSCs transplantation group (MI+CD73 + ADMSCs) and CD73 - ADMSCs transplantation group (MI+CD73 - ADMSCs). CD73 + ADMSCs were isolated using flow cytometry and then cultured. Overexpression and inhibition of CD73 gene of ADMSCs using lentiviral vectors. Differential genes analysis of CD73 + ADMSCs vs. CD73 - ADMSCs were based on GO analysis. The effect of CD73 on the secretion of cytokines was measured by ELISA. Myocardial infarction model and cell transplantation model were replicated. Detection of cardiac function of rats by color doppler ultrasound after operation. The expression of VEGF and factor VIII and neovascularization were detected by immunohistochemistry and Western Blotting. Results: We demonstrated that, compared to mixed ADMSCs and CD73 - ADMSCs, CD73 + ADMSCs were more effective in the promotion function of cardiac recovery in a rat model of MI. CD73 + subset promoted vascular regeneration in myocardial injured regions. We also showed that expression of CD73 promoted secretion of VEGF, HIF-1α and HGF factors in ADMSCs. CD73 + ADMSCs displayed significantly different transcription profile compared to CD73 - ADMSCs, in particular, concerning VEGF pathways. Conclusions: Overall, CD73 + ADMSCs were the dominant subgroup and the presence of the surface marker CD73 can be used as a MSCs cell quality control for treatment of myocardial injury by angiogenesis.

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