Restoration of Cardiac Function with Progenitor Cells

2008 ◽  
pp. 214-227 ◽  
Author(s):  
Carmen Urbich ◽  
Lothar Rössig ◽  
Stefanie Dimmeler
Keyword(s):  
Cardiac Function ◽  
Progenitor Cells

Abstract 247: Scaffold-stiffness Dependent Notch1 Activation Regulates Cardiogenic Gene Expression In Cardiac Progenitor Cells

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Archana V Boopathy ◽  
Pao L Che ◽  
Yoshie Narui ◽  
Khalid Salaita ◽  
Michael E Davis
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Cardiac Function ◽  
Progenitor Cells ◽  
Adult Stem Cells ◽  
Cardiac Progenitor Cells ◽  
Critical Pathway ◽  
Cardiac Gene Expression ◽  
Self Assembling ◽  
Cardiac Gene

Rationale: Cardiac progenitor cells (CPCs) are multipotent, self-renewing cells that can regenerate the myocardium and improve cardiac function in animal models of myocardial infarction (MI). However, limited survival of stem/progenitor cells inhibits cardiac regeneration. Force dependent Notch activation promotes cardiac development and cardiac gene expression in many adult stem cells. As dysregulation of Notch signaling leads to embryonic lethal cardiovascular defects, activating this critical pathway during cell transplantation could improve efficacy of stem cell therapy. Objective: Investigate i) whether self-assembling peptide scaffolds can be used to activate Notch1 signaling in CPCs to promote cardiogenic differentiation and ii) the effect of scaffold stiffness on Notch1 activation and differentiation. Methods: Rat CPCs (c-kit + ) were cultured for 48h in 3D self-assembling scaffolds of varying stiffness (1% low, 2% high): empty scaffolds (RADA), scaffolds modified with peptide mimicking Notch1 ligand, Jagged1 (RJAG), or scaffolds modified with a scrambled peptide (RSCR) and cardiogenic gene expression measured by qRT-PCR. CHO cells expressing Notch1 responsive YFP were also cultured in the above scaffolds for 48h and YFP expression was determined. Results are mean ± SEM with p<0.05 considered significant by one or two-way ANOVA with appropriate post test. Results: In the Notch1 reporter cells, Notch1 activation increased significantly in presence of RJAG (p<0.01) and on increasing scaffold stiffness (p<0.01,n=6) indicating scaffold stiffness-dependent Notch1 activation. Culture of CPCs in RJAG containing 1% scaffolds (low stiffness) significantly increased early endothelial and smooth muscle but not cardiac gene expression while in 2% scaffolds (high stiffness) significantly increased only cardiac and not endothelial or smooth muscle gene expression (p<0.05, n≥4). Conclusions: Taken together, these data show that i) Notch1 activation in 3D is dependent on ligand density and scaffold stiffness and ii) stiffness dependent Notch1 activation differentially regulates cardiogenic gene expression in CPCs. Therefore, delivery of CPCs in JAG containing scaffolds could be used to improve cardiac function following MI.

Abstract 212: Aggregation of Child Cardiac Progenitor Cells into 3D Spheres Improves Endothelial Lineage Commitment

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
David Q Trac ◽  
Chunhui Xu ◽  
Michael E. Davis
Keyword(s):  
Stem Cell ◽  
Cardiac Function ◽  
Notch Signaling ◽  
Progenitor Cells ◽  
Gene Array ◽  
Lineage Commitment ◽  
Cardiac Progenitor Cells ◽  
Notch Ligand ◽  
Monolayer Cultures ◽  
Endothelial Lineage

Congenital heart disease is rarely cured by surgery and can lead to life-threatening, intractable right ventricular heart failure (HF). In particular, children with hypoplastic left heart syndrome have a 10 year transplant-free survival rate of 50-75% despite palliative surgical repair. Currently, no effective stem-cell based treatments are available for pediatric HF. Recent stem-cell based clinical trials have been limited by poor differentiation rates and low cell retention. Additionally, we have shown that human cardiac progenitor cells (hCPCs) have reduced regenerative potential as they age, starting as early as 1 year old. We propose the aggregation of CPCs into scaffold-free spheres to improve the differentiation of child CPCs into mature cardiac phenotypes by enhancing intercellular Notch signaling. Notch signaling activity has been implicated in the regulation of CPC fate decisions and prior research in our lab has shown that intramyocardial delivery of Notch-ligand containing hydrogels improves cardiac function. Child CPC spheres were produced at a size of 1500 cells per sphere using a microwell array and cultured in suspension. Using immunohistochemistry, we showed that aggregation of CPCs increased Notch1 expression compared to parallel monolayer cultures. This effect is not limited to CPCs and was recapitulated in spheres of Chinese hamster ovarian cells transfected with Notch1-YFP. Additionally, Notch signaling pathway gene array data showed increased expression of the Notch-cleaving metalloprotease ADAM10 (3.6-fold) and Notch ligand DLL1 (25.0-fold) in CPC spheres by 3 days in culture compared to monolayer cultures. By 14 days in culture, we showed that aggregation of CPCs robustly increases the expression of the GATA4, a cardiac transcription factor associated with angiogenesis, and VEGFR1, an early marker of endothelial lineage commitment. Based on our results, we hypothesize that aggregation of CPCs into spheroids increases endothelial differentiation via a Notch-dependent mechanism. Transplantation of CPC spheres may improve cardiac function in vivo compared to transplantation of single CPCs. The results from our project will facilitate the development of autologous stem-cell based therapies for pediatric HF.

scholarly journals Transplantation of Endothelial Progenitor Cells in the Treatment of Coronary Artery Microembolism in Rats

2020 ◽  
Vol 29 ◽  
pp. 096368972091268
Author(s):  
Yajun Xue ◽  
Boda Zhou ◽  
Jian Wu ◽  
Guobin Miao ◽  
Kun Li ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Function ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Low Dose ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
High Dose ◽  
Endothelial Progenitor ◽  
Ventricular Ejection Fraction

As the impairment of myocardial microenvironments due to coronary microembolization (CME) compromises the treatment effect of percutaneous coronary intervention and leads to adverse prognosis, we hypothesized that endothelial progenitor cells (EPCs) transplantation could improve cardiac function in the condition of CME. Low- (2 × 105) and high- (2 × 106) dose rat bone marrow-derived EPCs were transplanted in a model of CME. To develop a CME model, rats were injected with autologous micro-blood-clots into the left ventricle. Echocardiograph was examined before and 1, 7, and 28 days after EPC transplantation; serum cardiac troponin I (cTNI), von Willebrand factor (vWF), and cardiac microRNA expression were examined one day after EPCs transplantation. Heart morphology and vascular endothelial growth factor (VEGF), vWF, and basic fibroblast growth factor (bFGF) expression were examined one day after EPC transplantation. After 10 days of culture inductions, BM-EPCs have high purity as confirmed by flow cytometry. Cardiac function reflected by left ventricular ejection fraction significantly decreased after CME treatment and rescued by low-dose EPC. Compared to the sham group, cTNI and vWF serum levels increased significantly after CME treatment and rescued by low-dose EPC and high-dose EPC. Low-dose EPC treatment decreased myocardial necrosis and fibrosis and elevated cardiac expression of VEGF and vWF, while decreasing the cardiac expression of bFGF. Low-dose EPC treatment significantly suppressed cardiac expression of microRNA-19a but significantly enhanced microRNA-21, microRNA-214, and microRNA-486-3p expression. In conclusion, our results indicate that low-dose EPC transplantation may play a proangiogenic, antifibroblast, antifibrosis, and antinecrosis role and enhance cardiac function in a rat model of CME through a microRNA-related pathway.

scholarly journals MicroRNA-326-5p enhances therapeutic potential of endothelial progenitor cells for myocardial infarction

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiaoting Li ◽  
Xiang Xue ◽  
Yuejun Sun ◽  
Lei Chen ◽  
Ting Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Western Blot ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Tube Formation ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Reporter Assay

Abstract Background Our study sought to investigate the therapeutic effects and mechanisms of miR-326-5p-overexpressing endothelial progenitor cells (EPCs) on acute myocardial infarction (AMI). Methods Mouse EPCs were isolated, purified, and identified by flow cytometry and uptake of DiI-ac-LDL. The target gene of miR-326-5p was predicted using target prediction algorithms and verified by dual-luciferase reporter assay, RT-qPCR, and Western blot. After EPCs were transfected with the agomir or antagomir of miR-326-5p, tube formation assay and Matrigel plug angiogenesis assay were conducted in four groups (NC, miR-326-5p agomir, miR-326-5p antagomir, and miR-326-5p agomir+Wnt1 agonist). In addition, a mouse model of MI was established and treated with the injection of miR-326-5p-EPCs, miR-326-5p-EPCs+ Wnt1 agonist, EPCs-NC, or PBS/control into the peri-infarcted myocardium. Subsequently, cardiac function was monitored by echocardiography at 7 and 28 days postoperatively. Finally, the infarcted hearts were collected at 28 days, and the size of myocardial infarction was measured by Masson’s trichrome staining and the neovascularization in the peri-infarcted area was examined through immunofluorescence staining. Results Luciferase reporter assay indicated that Wnt1 was a direct target of miR-326-5p. Using RT-qPCR and Western blot analysis, we further demonstrated that the expression level of Wnt1 was negatively correlated with miR-326-5p expression in EPCs. Both in vitro study of tube formation assay and in vivo investigation of subcutaneous Matrigel plug assay revealed that the miR-326-5p agomir could significantly enhance the angiogenic capacity of EPCs, and this effect was partially inhibited by Wnt1 agonist. Meanwhile, miR-326-5p antagomir could obviously reduce the the angiogenic capacity of EPCs in vivo compared with that in the NC group. Moreover, the transplantation of miR-326-5p-overexpressing EPCs in the ischemic hearts of mice significantly enhanced the angiogenesis in the peri-infarcted zone and improved the cardiac function. However, the enhanced capacity of angiogenesis of miR-326-5p-overexpressing EPCs was remarkably neutralized by Wnt1 agonist, accompanied by the decreased improvement in cardiac function. Conclusion miR-326-5p significantly enhanced the angiogenic capacity of EPCs. Transplantation of miR-326-5p-overexpressing EPCs improved cardiac function for AMI therapy, which can be a novel strategy for enhancing therapeutic angiogenesis in ischemic heart diseases.

scholarly journals Local Activation or Implantation of Cardiac Progenitor Cells Rescues Scarred Infarcted Myocardium Improving Cardiac Function

2008 ◽  
Vol 103 (1) ◽  
pp. 107-116 ◽  
Author(s):  
Marcello Rota ◽  
M. Elena Padin-Iruegas ◽  
Yu Misao ◽  
Antonella De Angelis ◽  
Silvia Maestroni ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Progenitor Cells ◽  
Cardiac Progenitor Cells ◽  
Local Activation ◽  
Infarcted Myocardium

scholarly journals Electromechanical Conditioning of Adult Progenitor Cells Improves Recovery of Cardiac Function After Myocardial Infarction

2016 ◽  
Vol 6 (3) ◽  
pp. 970-981 ◽  
Author(s):  
Aida Llucià-Valldeperas ◽  
Carolina Soler-Botija ◽  
Carolina Gálvez-Montón ◽  
Santiago Roura ◽  
Cristina Prat-Vidal ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Progenitor Cells
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