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Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction.

Paul A, Nayan M, Khan AA, Shum-Tim D, Prakash S - Int J Nanomedicine (2012)

Bottom Line: The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes.The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups.A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, QC, Canada.

ABSTRACT
The objective of this study was to develop angiopoietin-1 (Ang1)-expressing genetically modified human adipose tissue derived stem cells (hASCs) for myocardial therapy. For this, an efficient gene delivery system using recombinant baculovirus complexed with cell penetrating transactivating transcriptional activator TAT peptide/deoxyribonucleic acid nanoparticles (Bac-NP), through ionic interactions, was used. It was hypothesized that the hybrid Bac- NP(Ang1) system can efficiently transduce hASCs and induces favorable therapeutic effects when transplanted in vivo. To evaluate this hypothesis, a rat model with acute myocardial infarction and intramyocardially transplanted Ang1-expressing hASCs (hASC-Ang1), genetically modified by Bac-NP(Ang1), was used. Ang1 is a crucial pro-angiogenic factor for vascular maturation and neovasculogenesis. The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes. The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups. A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group. Furthermore, the hASC-Ang1 group showed significantly higher cardiac performance in echocardiography (ejection fraction 46.28% ± 6.3%, P < 0.001 versus control, n = 8) than the hASC group (36.35% ± 5.7%, P < 0.01, n = 8), 28 days post-infarction. The study identified Bac-NP complex as an advanced gene delivery vehicle for stem cells and demonstrated its potential to treat ischemic heart disease with high therapeutic index for combined stem cell-gene therapy strategy.

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(A) Histomorphometric analysis of infarct ventricular scar area. (i–iv) Representative images of left ventricle myocardial sections stained with Masson’s trichrome show the markedly decreased cardiac fibrosis after hASC and hASC-Ang1 transplantations 28 days post-infarction compared to the control. The blue area represents extracellular matrix deposition in the scar tissue and the red area represents the myocardium. (B) Semiquantitative analysis of the images of the stained collagen fractions in the infarct region, using ImageJ 1.41 software (National Institutes of Health, Bethesda, MA), show that hASC and hASC-Ang1 transplantations significantly decreased cardiac fibrosis compared to untreated group (n = 8) in terms of percent infarction size in left ventricular wall. (C) Moreover, hASC and hASC-Ang1 groups have significantly thicker left ventricular walls than untreated group. In both analyses, hASC-Ang1 treatment proved to be significantly better than hASC treatment.Notes: Data expressed as mean ± standard deviation. One-way analysis of variance: (B) F = 101.3, P < 0.0001 and (C) F = 166.1, P < 0.0001 (treatment groups). Statistically significant differences between groups compared to control no hASC are indicated as ***P < 0.001; **P < 0.01; *P < 0.05. Significant difference between hASC and hASC-Ang1 is indicated by †P < 0.001.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.
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f6-ijn-7-663: (A) Histomorphometric analysis of infarct ventricular scar area. (i–iv) Representative images of left ventricle myocardial sections stained with Masson’s trichrome show the markedly decreased cardiac fibrosis after hASC and hASC-Ang1 transplantations 28 days post-infarction compared to the control. The blue area represents extracellular matrix deposition in the scar tissue and the red area represents the myocardium. (B) Semiquantitative analysis of the images of the stained collagen fractions in the infarct region, using ImageJ 1.41 software (National Institutes of Health, Bethesda, MA), show that hASC and hASC-Ang1 transplantations significantly decreased cardiac fibrosis compared to untreated group (n = 8) in terms of percent infarction size in left ventricular wall. (C) Moreover, hASC and hASC-Ang1 groups have significantly thicker left ventricular walls than untreated group. In both analyses, hASC-Ang1 treatment proved to be significantly better than hASC treatment.Notes: Data expressed as mean ± standard deviation. One-way analysis of variance: (B) F = 101.3, P < 0.0001 and (C) F = 166.1, P < 0.0001 (treatment groups). Statistically significant differences between groups compared to control no hASC are indicated as ***P < 0.001; **P < 0.01; *P < 0.05. Significant difference between hASC and hASC-Ang1 is indicated by †P < 0.001.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.

Mentions: Macroscopic views of Masson’s trichrome stained heart sections are shown in Figure 6A. In both the control and cell treated groups, positively stained fibrous infarct areas were clearly observed in the heart 28 days after myocardial infarction. Thin infarcts and left ventricular wall with dilated left ventricular cavity were observed in the control hearts. On the other hand, the hearts in the cell treated groups had significantly lesser infarct areas (Figure 6B: 13.0% ± 3.1% for hASC-Ang1, 31.5% ± 5.0% for hASCs, and 38.0% ± 3.3% for control; P < 0.01) and higher left ventricular wall thickness (Figure 6C: 2.53 ± 0.19 mm for hASC-Ang1, 1.44 ± 0.24 mm for hASCs, and 0.91 ± 0.07 mm for control; P < 0.001) than the control heart. A total of 24 rats were analyzed for the determination of infarct size (no hASC control [n = 8], hASCs [n = 8], and hASC-Ang1 [n = 8]). Infarct size and wall thickness in the left ventricles at the section of the middle point between ligation and apex were measured as described elsewhere.22 There was also a significant improvement in the group treated with hASC-Ang1 compared to hASCs group (P < 0.001) with respect to the percentage left ventricle infarct area and left ventricle infarct wall thickness.


Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction.

Paul A, Nayan M, Khan AA, Shum-Tim D, Prakash S - Int J Nanomedicine (2012)

(A) Histomorphometric analysis of infarct ventricular scar area. (i–iv) Representative images of left ventricle myocardial sections stained with Masson’s trichrome show the markedly decreased cardiac fibrosis after hASC and hASC-Ang1 transplantations 28 days post-infarction compared to the control. The blue area represents extracellular matrix deposition in the scar tissue and the red area represents the myocardium. (B) Semiquantitative analysis of the images of the stained collagen fractions in the infarct region, using ImageJ 1.41 software (National Institutes of Health, Bethesda, MA), show that hASC and hASC-Ang1 transplantations significantly decreased cardiac fibrosis compared to untreated group (n = 8) in terms of percent infarction size in left ventricular wall. (C) Moreover, hASC and hASC-Ang1 groups have significantly thicker left ventricular walls than untreated group. In both analyses, hASC-Ang1 treatment proved to be significantly better than hASC treatment.Notes: Data expressed as mean ± standard deviation. One-way analysis of variance: (B) F = 101.3, P < 0.0001 and (C) F = 166.1, P < 0.0001 (treatment groups). Statistically significant differences between groups compared to control no hASC are indicated as ***P < 0.001; **P < 0.01; *P < 0.05. Significant difference between hASC and hASC-Ang1 is indicated by †P < 0.001.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3278230&req=5

f6-ijn-7-663: (A) Histomorphometric analysis of infarct ventricular scar area. (i–iv) Representative images of left ventricle myocardial sections stained with Masson’s trichrome show the markedly decreased cardiac fibrosis after hASC and hASC-Ang1 transplantations 28 days post-infarction compared to the control. The blue area represents extracellular matrix deposition in the scar tissue and the red area represents the myocardium. (B) Semiquantitative analysis of the images of the stained collagen fractions in the infarct region, using ImageJ 1.41 software (National Institutes of Health, Bethesda, MA), show that hASC and hASC-Ang1 transplantations significantly decreased cardiac fibrosis compared to untreated group (n = 8) in terms of percent infarction size in left ventricular wall. (C) Moreover, hASC and hASC-Ang1 groups have significantly thicker left ventricular walls than untreated group. In both analyses, hASC-Ang1 treatment proved to be significantly better than hASC treatment.Notes: Data expressed as mean ± standard deviation. One-way analysis of variance: (B) F = 101.3, P < 0.0001 and (C) F = 166.1, P < 0.0001 (treatment groups). Statistically significant differences between groups compared to control no hASC are indicated as ***P < 0.001; **P < 0.01; *P < 0.05. Significant difference between hASC and hASC-Ang1 is indicated by †P < 0.001.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.
Mentions: Macroscopic views of Masson’s trichrome stained heart sections are shown in Figure 6A. In both the control and cell treated groups, positively stained fibrous infarct areas were clearly observed in the heart 28 days after myocardial infarction. Thin infarcts and left ventricular wall with dilated left ventricular cavity were observed in the control hearts. On the other hand, the hearts in the cell treated groups had significantly lesser infarct areas (Figure 6B: 13.0% ± 3.1% for hASC-Ang1, 31.5% ± 5.0% for hASCs, and 38.0% ± 3.3% for control; P < 0.01) and higher left ventricular wall thickness (Figure 6C: 2.53 ± 0.19 mm for hASC-Ang1, 1.44 ± 0.24 mm for hASCs, and 0.91 ± 0.07 mm for control; P < 0.001) than the control heart. A total of 24 rats were analyzed for the determination of infarct size (no hASC control [n = 8], hASCs [n = 8], and hASC-Ang1 [n = 8]). Infarct size and wall thickness in the left ventricles at the section of the middle point between ligation and apex were measured as described elsewhere.22 There was also a significant improvement in the group treated with hASC-Ang1 compared to hASCs group (P < 0.001) with respect to the percentage left ventricle infarct area and left ventricle infarct wall thickness.

Bottom Line: The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes.The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups.A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, QC, Canada.

ABSTRACT
The objective of this study was to develop angiopoietin-1 (Ang1)-expressing genetically modified human adipose tissue derived stem cells (hASCs) for myocardial therapy. For this, an efficient gene delivery system using recombinant baculovirus complexed with cell penetrating transactivating transcriptional activator TAT peptide/deoxyribonucleic acid nanoparticles (Bac-NP), through ionic interactions, was used. It was hypothesized that the hybrid Bac- NP(Ang1) system can efficiently transduce hASCs and induces favorable therapeutic effects when transplanted in vivo. To evaluate this hypothesis, a rat model with acute myocardial infarction and intramyocardially transplanted Ang1-expressing hASCs (hASC-Ang1), genetically modified by Bac-NP(Ang1), was used. Ang1 is a crucial pro-angiogenic factor for vascular maturation and neovasculogenesis. The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes. The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups. A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group. Furthermore, the hASC-Ang1 group showed significantly higher cardiac performance in echocardiography (ejection fraction 46.28% ± 6.3%, P < 0.001 versus control, n = 8) than the hASC group (36.35% ± 5.7%, P < 0.01, n = 8), 28 days post-infarction. The study identified Bac-NP complex as an advanced gene delivery vehicle for stem cells and demonstrated its potential to treat ischemic heart disease with high therapeutic index for combined stem cell-gene therapy strategy.

Show MeSH
Related in: MedlinePlus