Adult Human Blood Leukocytes as a Source of Tissue-Committed Progenitors for Cellular Therapy of Cardiovascular Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 32-32 ◽  
Author(s):  
Yael Porat ◽  
Valetin Fulga ◽  
Danny Belkin ◽  
Daphna Shimoni ◽  
Adina Belleli ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Progenitor Cells ◽  
Cell Population ◽  
Autologous Serum ◽  
Therapeutic Effects ◽  
Stem Cell Markers ◽  
Blood Leukocytes

Abstract Significant progress has been made in recent years in developing therapeutic strategies for the treatment of a variety of cardiovascular disorders, mainly using bone marrow-derived progenitor cells. We hypothesized that blood leukocytes can also serve as a source for a wide range of clinical protocols. We report here the generation in vitro of both angiogenic cell precursors (ACP) and cardiomyocyte (CMC) progenitors from a newly discovered blood-derived multipotent cell population, termed synergetic cell population (SCP), and their function in vitro and in vivo. Progenitor cells were purified from healthy donor blood samples using density-based gradients. SCP-derived ACPs grown in the presence of autologous serum and VEGF exhibited an elongated, spindle-shaped morphology and expressed the stem cell markers CD34 (an average of 23.1% of cells), CD133 (10.2%), and CD117 (10.8%), and the endothelial markers KDR (8.9%), Tie-2 (24.8%), CD144 (41.2%), and CD31 (83.1%). Up to 30% of the cells exhibited Dil-Ac-LDL uptake, typical of endothelial cells. In vitro, ACPs showed organization into capillary tube structures when plated on extracellular matrix gels. An average of 50x106 ACPs were generated from 450 ml blood. CMC progenitors, which resulted from culturing SCP cells in medium containing autologous serum and bFGF followed by activation in a medium containing 5-azacytidine, appeared elongated with dark cytoplasm and expressed the cardiomyocyte markers desmin and troponin (on 19.7% and 52.3% of cells, respectively). The therapeutic potential of blood derived ACPs is currently being evaluated in patients with severe angina pectoris. Seventeen patients on maximal drug therapy have so far been prospectively enrolled, based upon identifying ischemic but viable myocardium in distribution of the coronary arteries that were totally occluded. ACPs (25x106, SE=4.9) were injected via a catheter into the coronary artery. Preliminary results demonstrate safety and improved clinical symptoms at 3 months vs. baseline. Mean Canadian Cardiovascular Scale for angina severity decreased from 1.8±0.8 to 1.06±0.3 (P=0.062) and exercise capacity measured by metabolic equivalents increased from 6.3±2.3 to 7.4 ±2.8 (P= 0.0083). One patient died two weeks after the treatment due to acute myocardial infarction. However, coronary angiography demonstrated acute occlusion of an artery not treated with cells. These results suggest the treatment is safe with preliminary short term beneficial effect. Continued follow-up is currently being conducted to determine the long-term effects of this therapy in a larger number of patients. In order to examine the functional mechanisms underlying the therapeutic effects of ACPs and CMC progenitors, an in-vivo experiment is also being carried out in a nude rat acute myocardial infarction model. We demonstrate here that a newly-discovered multipotent cell population which we term SCP can be isolated from peripheral blood and differentiated into therapeutically effective tissue-committed progenitor cells. The SCP contains hematopoietic stem cells and supportive cells enabling differentiation into various lineages, such as ACPs, cardiomyocyte and neural progenitors (the latter reported in a separate abstract by our group) which have thus been generated.

Clinical Trials in Thrombosis: Secondary Prevention of Myocardial Infarction

1976 ◽  
Vol 35 (01) ◽  
pp. 049-056 ◽  
Author(s):  
Christian R Klimt ◽  
P. H Doub ◽  
Nancy H Doub
Keyword(s):  
Myocardial Infarction ◽  
Secondary Prevention ◽  
Case Control ◽  
Therapeutic Effects ◽  
Case Control Studies ◽  
Definitive Answer ◽  
Inhibition Of Platelet Aggregation ◽  
Prospective Trials

SummaryNumerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that antiplatelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

scholarly journals Novel Identified Circular Transcript of RCAN2, circ-RCAN2, Shows Deviated Expression Pattern in Pig Reperfused Infarcted Myocardium and Hypoxic Porcine Cardiac Progenitor Cells In Vitro

2021 ◽  
Vol 22 (3) ◽  
pp. 1390
Author(s):  
Julia Mester-Tonczar ◽  
Patrick Einzinger ◽  
Johannes Winkler ◽  
Nina Kastner ◽  
Andreas Spannbauer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Progenitor Cells ◽  
Regulatory Networks ◽  
Circular Rnas ◽  
Cardiac Progenitor Cells ◽  
Tissue Samples ◽  
Healthy Myocardium ◽  
Acute Mi

Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.

Ex vivo-expanded bone marrow CD34+ for acute myocardial infarction treatment: in vitro and in vivo studies

Cytotherapy ◽  
2011 ◽  
Vol 13 (9) ◽  
pp. 1140-1152 ◽  
Author(s):  
Monica Gunetti ◽  
Alessio Noghero ◽  
Fabiola Molla ◽  
Lidia Irene Staszewsky ◽  
Noeleen de Angelis ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Bone Marrow ◽  
Ex Vivo ◽  
In Vivo Studies

scholarly journals Network pharmacology-based identification of major component of Angelica sinensis and its action mechanism for the treatment of acute myocardial infarction

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Xiaowei Niu ◽  
Jingjing Zhang ◽  
Jinrong Ni ◽  
Runqing Wang ◽  
Weiqiang Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Er Stress ◽  
Heart Function ◽  
Network Pharmacology ◽  
Angelica Sinensis ◽  
Peroxisome Proliferator ◽  
Multiple Targets

Background: To decipher the mechanisms of Angelica sinensis for the treatment of acute myocardial infarction (AMI) using network pharmacology analysis. Methods: Databases were searched for the information on constituents, targets, and diseases. Cytoscape software was used to construct the constituent–target–disease network and screen the major targets, which were annotated with the DAVID (Database for Annotation, Visualization and Integrated Discovery) tool. The cardioprotective effects of Angelica sinensis polysaccharide (ASP), a major component of A. sinensis, were validated both in H9c2 cells subjected to simulated ischemia by oxygen and glucose deprivation and in rats with AMI by ligation of the left anterior coronary artery. Results: We identified 228 major targets against AMI injury for A. sinensis, which regulated multiple pathways and hit multiple targets involved in several biological processes. ASP significantly decreased endoplasmic reticulum (ER) stress-induced cell death both in vitro and in vivo. In ischemia injury rats, ASP treatment reduced infarct size and preserved heart function. ASP enhanced activating transcription factor 6 (ATF6) activity, which improved ER-protein folding capacity. ASP activated the expression of p-AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Additionally, ASP attenuated levels of proinflammatory cytokines and maintained a balance in the oxidant/antioxidant levels after AMI. Conclusion:In silico analysis revealed the associations between A. sinensis and AMI through multiple targets and several key signaling pathways. Experimental data indicate that ASP protects the heart against ischemic injury by activating ATF6 to ameliorate the detrimental ER stress. ASP’s effects could be mediated via the activation of AMPK-PGC1α pathway.

scholarly journals Effects of Sodium Nitroprusside on Platelet Adhesion, Subsequent Aggregation and Vasoconstriction

1977 ◽  
Author(s):  
H.R. Baumgartner
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Sodium Nitroprusside ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Balloon Catheter ◽  
Strong Inhibitor ◽  
Induced Aggregation

Sodium nitroprusside (SNP), a potent vasodilator, has shown beneficial effects in acute myocardial infarction. Since platelets may play an important role in the pathogenesis of myocardial infarction, the effect of SNP on their interaction with rabbit aorta subendothelium was investigated in vivo and under controlled blood flow conditions ex vivo and in vitro.One iliac artery and the abdominal aorta were denuded of endothelium by balloon catheter injury during infusion of glucose, SNP at 6 or 12 μg/kg/min in groups of 12, 6 and 7 rabbits respectively. The aorta and their branches were perfuse-fixed under controlled pressure 10 min after denudation. Morphometric evaluation showed dose-dependent and significant (2p < 0.01 or 0.001) inhibition of platelet spreading, adhesion and aggregation. The latter was abolished at the higher dose of SNP. Denudation and subsequent platelet adhesion caused strong vasoconstriction (2p < 0.001) which was inhibited by SNP (2p < 0.01).By exposure of subendothelium to either citrated blood or native blood in a flow chamber (2000 sec-1 shear rate) strong inhibition of spreading and adhesion-induced aggregation was again demonstrated at 6 and 12 μg/kg/min SNP. In vitro, adhesion-induced aggregation was completely abolished after the addition of SNP to rabbit (at 20 μg/ml) or human blood (2 μg/ml). 1 μg/ml PGE1 was needed to induce a similar inhibitory effect.Thus SNP is a strong inhibitor of platelet function and of injury + platelet induced vasoconstriction. These findings may explain its beneficial effect in acute myocardial infarction.

scholarly journals Cardiac Mesenchymal Cells Cultured at Physiologic Oxygen Tension Have Superior Therapeutic Efficacy in Heart Failure Caused by Myocardial Infarction

2021 ◽  
Vol 9 ◽  
Author(s):  
Robi A. R. Bolli ◽  
Asma Arshia ◽  
Syed A. Hassan ◽  
Chandrashekhar Dasari ◽  
Yibing Nong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Progenitor Cells ◽  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Mesenchymal Cells ◽  
Intraventricular Injection ◽  
Lv Function

Stem/progenitor cells are usually cultured at atmospheric O2 tension (21%); however, since physiologic O2 tension in the heart is ∼5%, using 21% O2 may cause oxidative stress and toxicity. Cardiac mesenchymal cells (CMCs), a newly discovered and promising type of progenitor cells, are effective in improving left ventricle (LV) function after myocardial infarction (MI). We have previously shown that, compared with 21% O2, culture at 5% O2 increases CMC proliferation, telomerase activity, telomere length, and resistance to severe hypoxia in vitro. However, it is unknown whether these beneficial effects of 5% O2in vitro translate into greater therapeutic efficacy in vivo in the treatment of heart failure. Thus, murine CMCs were cultured at 21% or 5% O2. Mice with heart failure caused by a 60-min coronary occlusion followed by 30 days of reperfusion received vehicle, 21% or 5% O2 CMCs via echocardiography-guided intraventricular injection. After 35 days, the improvement in LV ejection fraction effected by 5% O2 CMCs was &gt; 3 times greater than that afforded by 21% O2 CMCs (5.2 vs. 1.5 units, P &lt; 0.01). Hemodynamic studies (Millar catheter) yielded similar results both for load-dependent (LV dP/dt) and load-independent (end-systolic elastance) indices. Thus, two independent approaches (echo and hemodynamics) demonstrated the therapeutic superiority of 5% O2 CMCs. Further, 5% O2 CMCs, but not 21% O2 CMCs, significantly decreased scar size, increased viable myocardium, reduced LV hypertrophy and dilatation, and limited myocardial fibrosis both in the risk and non-infarcted regions. Taken together, these results show, for the first time, that culturing CMCs at physiologic (5%) O2 tension provides superior therapeutic efficacy in promoting cardiac repair in vivo. This concept may enhance the therapeutic potential of CMCs. Further, culture at 5% O2 enables greater numbers of cells to be produced in a shorter time, thereby reducing costs and effort and limiting cell senescence. Thus, the present study has potentially vast implications for the field of cell therapy.

scholarly journals Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis

2021 ◽  
Author(s):  
Hogjuan Ning ◽  
Haixu Chen ◽  
Jingyu Deng ◽  
Chun Xiao ◽  
Lina Shan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathway ◽  
Transmembrane Protein ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Therapeutic Effects ◽  
Cell Based Therapy ◽  
Anti Inflammation

Abstract Background Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secreted more exosomes, but little was known on MI repair. Methods Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis, and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. Results Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs–Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF-κB signaling pathway and upregulated Nrf2/HO-1 Axis. Conclusions FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.

Abstract 217: Long Non-coding RNA Myocardial Infarction-associated Transcript (MIAT) Protects Cardiac Progenitor Cells From Oxidative Stress-induced Cell Death

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Liu Yang ◽  
Yang Yu ◽  
Baron Arnone ◽  
Chan Boriboun ◽  
Jiawei Shi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cell Death ◽  
Progenitor Cells ◽  
Cardiac Cells ◽  
Border Zone ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells

Background: Long non-coding RNAs (lncRNAs) are an emerging class of RNAs with no or limited protein-coding capacity; a few of which have recently been shown to regulate critical biological processes. Myocardial infarction-associated transcript (MIAT) is a conserved mammalian lncRNA, and single nucleotide polymorphisms (SNPs) in 6 loci of this gene have been identified to be strongly associated with the incidence and severity of human myocardial infarction (MI). However, whether and how MIAT impacts on the pathogenesis of MI is unknown. Methods & Results: Quantitative RT-PCR analyses revealed that MIAT is expressed in neonatal mouse heart and to a lesser extent in adult heart. After surgical induction of MI in adult mice, MIAT starts to increase in 2 hours, peaks at 6 hours in atria and 12 hours in ventricles, and decreases to baseline at 24 hours. Fluorescent in situ hybridization (FISH) revealed a slight increase in the number of MIAT-expressing cells in the infarct border zone at 12 hours post-MI. Moreover, qRT-PCR analyses of isolated cardiac cells revealed that MIAT is predominantly expressed in cardiosphere-derived cardiac progenitor cells (CPCs). Treatment of CPCs with H 2 O 2 led to a marked upregulation of MIAT, while knockdown (KD) of MIAT resulted in a significantly impaired cell survival in vitro with H 2 O 2 treatment and in vivo after administered in the ischemic/reperfused heart. Notably, bioinformatics prediction and RNA immunoprecipitation identified FUS (fused in sarcoma) as a novel MIAT-interacting protein. FUS-KD CPCs displayed reduced cell viability and increased apoptosis under oxidative stress. Furthermore, MIAT overexpression enhanced survival of WT CPCs but not FUS-KD CPCs, suggesting that the protective role of MIAT is mediated by FUS. Conclusions: MIAT interacts with FUS to protect CPCs from oxidative stress-induced cell death.

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