Adipose-derived stem cells are an effective cell candidate for treatment of heart failure: an MR imaging study of rat hearts

2009 ◽  
Vol 297 (3) ◽  
pp. H1020-H1031 ◽  
Author(s):  
Lei Wang ◽  
Jixian Deng ◽  
Weichen Tian ◽  
Bo Xiang ◽  
Tonghua Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Cardiac Function ◽  
Recovery Period ◽  
Capillary Density ◽  
Left Ventricular ◽  
Border Zone ◽  
Wall Thickening ◽  
Adipose Derived Stem Cells ◽  
Rat Hearts

This study assessed the potential therapeutic efficacy of adipose-derived stem cells (ASCs) on infarcted hearts. Myocardial infarction was induced in rat hearts by occlusion of the left anterior descending artery (LAD). One week after LAD occlusion, the rats were divided into three groups and subjected to transplantation of ASCs or transplantation of cell culture medium (CCM) or remained untreated. During a 1-mo recovery period, magnetic resonance imaging showed that the ASC-treated hearts had a significantly greater left ventricular (LV) ejection fraction and LV wall thickening than did the CCM-treated and untreated hearts. The capillary density in infarct border zone was significantly higher in the ASC-treated hearts than in the CCM-treated and untreated hearts. However, only 0.5% of the ASCs recovered from the ASC-treated hearts were stained positive for cardiac-specific fibril proteins. It was also found that ASCs under a normal culture condition secreted three cardiac protective growth factors: vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1. Results of this study suggest that ASCs were able to improve cardiac function of infarcted rat hearts. Paracrine effect may be the mechanism underlying the improved cardiac function and increased capillary density.

Abstract 3899: SDF-1α Mediates the Therapeutic Effect of Human Adipose-Derived Stem Cells on Acute Myocardial Infarction Recruiting Bone Marrow-Derived Endothelial Progenitor Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masaaki Ii ◽  
Ayumi Yokoyama ◽  
Miki Horii ◽  
Hiroshi Akimaru ◽  
Takayuki Asahara
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Cardiac Function ◽  
Therapeutic Effect ◽  
Heart Diseases ◽  
Capillary Density ◽  
Ischemic Myocardium ◽  
Control Group ◽  
Adipose Derived Stem Cells ◽  
Ischemic Heart Diseases

Background: Recently, human multipotent adipose-derived stem cells (hMADSs) have been isolated featuring extensive expansion capacity ex vivo. However, little is known about the therapeutic efficacy of hMADS in ischemic heart diseases. We tested the hypothesis that hMADS transplantation may contribute to cardiac functional recovery following myocardial infarction (MI). Methods and Results: Nude rats were either transplanted with hMADSs (5x10 5 /rat, n=10) or PBS (control, n=9) in ischemic myocardium immediately following MI induction. The cardiac function, infarct size and capillary density in the peri-infarct area were evaluated by echocardiography and immunostaining 28 days after surgery. The cardiac function was significantly greater with increased capillary density and reduced fibrosis area in the hMADS group than that in the control group. Next, we examined tissue regeneration in the infarct heart by the transplanted hMADSs. However, remarkable differentiation of hMADSs into any cardiac cell lineages was not detected. To explore another mechanism for the favorable effect of hMADSs, we further examined mRNA expression of cytokines in hMADSs under hypoxic conditions. Although hypoxia decreased the expressions, robust VEGF, bFGF, and SDF-1α expressions were detected in hMADSs. Notably, the stem/progenitor chemokine SDF-1α expression in hMADSs was significantly greater than that in human mesenchymal stem cells that are well known to have a therapeutic effect on ischemic heart diseases. We then focused on SDF-1α /CXCR4 axis and examined the contribution of bone marrow (BM)-derived endothelial progenitor cells (EPCs), that have CXCR4 receptor for SDF-1v, to ischemic myocardium using a Tie2/LacZ BM transplantation nude mouse model. β-gal positive EPCs are frequently observed in ischemic myocardium in the hMADS group compared to the control group. Conclusion: hMADSs exhibit a therapeutic effect on cardiac function following MI with the production of VEGF, bFGF, and SDF-1α demonstrating paracrine effects rather than direct contribution to cardiac regeneration. These findings suggest that transplanted hMADSs and recruited EPCs may synergistically promote angiogenesis playing a role in ischemic myocardium.

Abstract 394: E2F1 Suppresses Cardiac Neovascularization by Downregulating VEGF and PlGF Expression

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Min Wu ◽  
Junlan Zhou ◽  
Min Cheng ◽  
Chan Boriboun ◽  
Dauren Biyashev ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Growth Factor ◽  
Cell Growth ◽  
Cardiac Function ◽  
Cardiac Fibroblasts ◽  
Vascular Endothelial Cell ◽  
Capillary Density ◽  
Border Zone ◽  
Vegf Receptor ◽  
Hypoxic Conditions

Objective: The E2F transcription factors are best characterized for their roles in cell-cycle regulation, cell growth, and cell survival. Here we investigated the potential role of E2F1 in cardiac neovascularization. Methods and Results: Myocardial infarction (MI) was induced in WT and E2F1 -/- mice. Compared to observations in WT mice, cardiac function, capillary density, and endothelial-cell (EC) proliferation were greater (P<0.01), infarct sizes were smaller (P<0.01), apoptotic ECs were less common (P<0.01); border-zone levels of vascular endothelial-cell growth factor (VEGF) (P<0.05) and placental growth factor (PlGF) (P<0.01) were higher; and border-zone p53 levels were lower (P<0.01); in E2F1 -/- mice. Blockade of VEGF receptor 2 (VEGFR2) signaling with the selective inhibitor SU5416 or with the VEGFR2-blocking antibody DC101 abolished the differences between E2F1 -/- mice and WT mice in cardiac function, infarct size, capillary density, EC proliferation, and EC apoptosis. Hypoxia-induced VEGF and PlGF upregulation was significantly greater in E2F1 -/- than in WT cardiac fibroblasts, and E2F1 overexpression suppressed PlGF upregulation in both WT and p53 -/- cells; however, VEGF upregulation was suppressed only in WT cells. E2F1 interacted with and stabilized p53 under hypoxic conditions, and both E2F1:p53 binding and the E2F1-induced suppression of VEGF promoter activity were absent in cells that expressed an N-terminally truncated E2F1 mutant. Conclusions: E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PlGF upregulation through p53-dependent and -independent mechanisms, respectively.

scholarly journals Pharmacological priming of adipose-derived stem cells promotes myocardial repair

2016 ◽  
Vol 64 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Jana S Burchfield ◽  
Ashley L Paul ◽  
Vishy Lanka ◽  
Wei Tan ◽  
Yongli Kong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Function ◽  
Functional Recovery ◽  
Cardiac Myocyte ◽  
Left Ventricular ◽  
Adipose Derived Stem Cells ◽  
Myocardial Repair ◽  
Myocyte Differentiation

Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.

Abstract 242: Bone-derived Stem Cells Repair The Heart After Myocardial Infarction Through Transdifferentiation And Paracrine Signaling Mechanisms

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jason M Duran ◽  
Catherine A Makarewich ◽  
Thomas E Sharp ◽  
Timothy Starosta ◽  
Fang Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Cardiac Function ◽  
Cell Function ◽  
Calcium Currents ◽  
Border Zone ◽  
Sham Operation ◽  
Paracrine Factors

Rationale: Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but has only offered limited functional improvements. Finding the optimal stem cell type best suited for cardiac regeneration remains a key goal toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone stem cells (CBSCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=57) or saline (n=59). Cardiac function was monitored using echocardiography with strain analysis. EGFP+ stem cells in vivo were shown to express only 2/8 factors tested (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, attenuated adverse remodeling, and decreased infarct size relative to saline-treated MI controls. By 6 weeks post-MI, EGFP+ cardiomyocytes, vascular smooth muscle cells and endothelial cells could be identified on histology. Isolated EGFP+ myocytes were smaller, more frequently mononucleated, and demonstrated fractional shortening and calcium currents indistinguishable from EGFP- myocytes from the same hearts. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling by 1) secreting the proangiogenic factors bFGF and VEGF (stimulating endogenous neovascularization), and 2) differentiating into functional adult myocytes and vascular cells.

Preservation of the cardiac function in infarcted rat hearts by the transplantation of adipose-derived stem cells with injectable fibrin scaffolds

2010 ◽  
Vol 235 (12) ◽  
pp. 1505-1515 ◽  
Author(s):  
Xuelian Zhang ◽  
Haibin Wang ◽  
Xiang Ma ◽  
Azhati Adila ◽  
Baozhu Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Function ◽  
Adipose Derived Stem Cells ◽  
Rat Hearts

scholarly journals Mesenchymal stem cells from human amniotic membrane differentiate into cardiomyocytes and endothelial-like cells without improving cardiac function after surgical administration in rat model of chronic heart failure

2019 ◽  
Vol 11 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Fazel Gorjipour ◽  
Ladan Hosseini-Gohari ◽  
Alireza Alizadeh Ghavidel ◽  
Seyed Javad Hajimiresmaiel ◽  
Nasim Naderi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Troponin T ◽  
Left Ventricular ◽  
Border Zone ◽  
Vascular Endothelial ◽  
Tissue Fibrosis

Introduction: Human amnion-derived mesenchymal stem cells (hAMSCs) have been used in the treatment of acute myocardial infarction. In the current study, we investigated the efficacy of hAMSCs for the treatment of chronic model of myocardial ischemia and heart failure (HF) in rats. Methods: Male Wistar rats weighing between 250 to 350 g were randomized into three groups: sham, HF control and HF+hAMSCs. For HF induction, animals were anesthetized and underwent left anterior descending artery ligation. In HF+hAMSCs group, 2×106 cells were injected into the left ventricular muscle four weeks post ischemia in the border zone of the ischemic area. Cardiac function was studied using echocardiography. Masson’s trichrome staining was used for studying tissue fibrosis. Cells were transduced with green fluorescent protein (GFP) coding lentiviral vector. Immunohistochemistry was used for detecting GFP, vascular-endothelial growth factor (VEGF) and troponin T markers in the tissue sections. Results: Assessment of the cardiac function revealed no improvement in the myocardial function compared to the control HF group. Moreover, tissue fibrosis was similar in two groups. Immunohistochemical study revealed the homing of the injected hAMSCs to the myocardium. Cells were stained positive for VEGF and troponin T markers. Conclusion: injection of hAMSCs 4 weeks after ischemia does not improve cardiac function and cardiac muscle fibrosis, although the cells show markers of differentiation into vascular endothelial cells and cardiomyocytes. In sum, it appears that hAMSCs are effective in the early phases of myocardial ischemia and does not offer a significant advantage in patients with chronic HF.

scholarly journals Bone-Derived Stem Cells Repair the Heart After Myocardial Infarction Through Transdifferentiation and Paracrine Signaling Mechanisms

2013 ◽  
Vol 113 (5) ◽  
pp. 539-552 ◽  
Author(s):  
Jason M. Duran ◽  
Catherine A. Makarewich ◽  
Thomas E. Sharp ◽  
Timothy Starosta ◽  
Fang Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Cardiac Function ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Border Zone ◽  
Sham Operation ◽  
Paracrine Factors

Rationale: Autologous bone marrow–derived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone–derived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells– or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC-treated, but not in cardiac-derived stem cells–treated, animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP− myocytes. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells.

Adipose-derived stem cells significantly improve cardiac function of the infarct rat hearts

2007 ◽  
Vol 42 (6) ◽  
pp. S97 ◽  
Author(s):  
L Wang ◽  
J Deng ◽  
G Li ◽  
J Wang ◽  
B Xiang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Function ◽  
Adipose Derived Stem Cells ◽  
Rat Hearts

Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells

2007 ◽  
Vol 292 (1) ◽  
pp. H522-H529 ◽  
Author(s):  
Fabrice Prunier ◽  
Otmar Pfister ◽  
Lahouria Hadri ◽  
Lifan Liang ◽  
Federica del Monte ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Left Ventricular Pressure ◽  
Capillary Density ◽  
Left Ventricular ◽  
Border Zone ◽  
High Dose ◽  
Area At Risk ◽  
Endothelial Progenitor ◽  
Volume Measurements ◽  
Infarct Border Zone

We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated 7 days after myocardial infarction (MI) in rats. A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The proangiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. In this study, rats underwent coronary occlusion followed by reperfusion or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) 0.75 μg/kg darbepoetin (MI+darb 0.75, n = 12); 2) 1.5 μg/kg darbepoetin (MI+darb 1.5, n = 12); 3) vehicle (MI+PBS, n = 16), once a week from day 7 postsurgery. Sham rats received the vehicle alone ( n = 10). After 8 wk of treatment, the animals underwent echocardiography, left ventricular pressure-volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured postmortem. The AAR was similar in the three MI groups. Compared with MI+PBS, the MI+darb 1.5 group showed a reduction in the MI-to-AAR ratio (20.8% vs. 38.7%; P < 0.05), as well as significantly reduced left ventricle dilatation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density ( P < 0.05) and by a higher number of EPC ( P < 0.05). Both darbepoetin doses increased the hematocrit, whereas MI+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. We found that chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone.

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