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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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Angiogenesis and arteriogenesis in the periinfarct area. Immunohistological staining of CD31 to detect endothelial cells in (A) no hASC, (B) hASC, and (C) hASC-Ang1 groups. Immunohistological staining of smooth muscle α-actin for smooth muscle cells in (D) no hASC, (E) hASC, and (F) hASC-Ang1 groups. Quantification of (G) capillary and (H) arteriole density.Notes: Data are expressed as mean ± standard deviation. One-way analysis of variance: (G) F = 24.86, P < 0.0001 and (H) F = 18.48, 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 †.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.
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f7-ijn-7-663: Angiogenesis and arteriogenesis in the periinfarct area. Immunohistological staining of CD31 to detect endothelial cells in (A) no hASC, (B) hASC, and (C) hASC-Ang1 groups. Immunohistological staining of smooth muscle α-actin for smooth muscle cells in (D) no hASC, (E) hASC, and (F) hASC-Ang1 groups. Quantification of (G) capillary and (H) arteriole density.Notes: Data are expressed as mean ± standard deviation. One-way analysis of variance: (G) F = 24.86, P < 0.0001 and (H) F = 18.48, 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 †.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.

Mentions: Reporting the significant attenuation of scar area with Ang1-expressing hASCs in the last section, attempts were made to understand whether it was only the paracrine effect of the hASCs or a combinatorial effect of hASC-released Ang1 and paracrine factors which was responsible for the improvement. For this, the neovasculature formation in the periinfarct area was assessed by detecting angiogenesis and arteriogenesis densities (Figure 7). Indeed, a significant improvement was seen in angiogenesis in the hASC and hASC-Ang1 groups compared to the control (201 ± 25/mm2 for hASC-Ang1, 174 ± 14/mm2 for hASCs, and 141.5 ± 6/mm2 for control; P < 0.01). Moreover, the hASC-Ang1 group showed significantly higher capillary density compared to hASC. Similar results were obtained with arteriole density in the hASC-Ang1 group (12.25 ± 2.4/mm2 for hASC-Ang1, 9.5 ± 1.8/mm2 for hASCs, and 6.5 ± 1.32/mm2 for control; P < 0.05), with the hASC-Ang1 group showing significantly higher arteriole density compared to hASC.


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)

Angiogenesis and arteriogenesis in the periinfarct area. Immunohistological staining of CD31 to detect endothelial cells in (A) no hASC, (B) hASC, and (C) hASC-Ang1 groups. Immunohistological staining of smooth muscle α-actin for smooth muscle cells in (D) no hASC, (E) hASC, and (F) hASC-Ang1 groups. Quantification of (G) capillary and (H) arteriole density.Notes: Data are expressed as mean ± standard deviation. One-way analysis of variance: (G) F = 24.86, P < 0.0001 and (H) F = 18.48, 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 †.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

Show All Figures
getmorefigures.php?uid=PMC3278230&req=5

f7-ijn-7-663: Angiogenesis and arteriogenesis in the periinfarct area. Immunohistological staining of CD31 to detect endothelial cells in (A) no hASC, (B) hASC, and (C) hASC-Ang1 groups. Immunohistological staining of smooth muscle α-actin for smooth muscle cells in (D) no hASC, (E) hASC, and (F) hASC-Ang1 groups. Quantification of (G) capillary and (H) arteriole density.Notes: Data are expressed as mean ± standard deviation. One-way analysis of variance: (G) F = 24.86, P < 0.0001 and (H) F = 18.48, 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 †.Abbreviations: hASC, human adipose tissue-derived cell; hASC-Ang1, angiopoietin-1-expressing human adipose tissue-derived cell; ctrl, control.
Mentions: Reporting the significant attenuation of scar area with Ang1-expressing hASCs in the last section, attempts were made to understand whether it was only the paracrine effect of the hASCs or a combinatorial effect of hASC-released Ang1 and paracrine factors which was responsible for the improvement. For this, the neovasculature formation in the periinfarct area was assessed by detecting angiogenesis and arteriogenesis densities (Figure 7). Indeed, a significant improvement was seen in angiogenesis in the hASC and hASC-Ang1 groups compared to the control (201 ± 25/mm2 for hASC-Ang1, 174 ± 14/mm2 for hASCs, and 141.5 ± 6/mm2 for control; P < 0.01). Moreover, the hASC-Ang1 group showed significantly higher capillary density compared to hASC. Similar results were obtained with arteriole density in the hASC-Ang1 group (12.25 ± 2.4/mm2 for hASC-Ang1, 9.5 ± 1.8/mm2 for hASCs, and 6.5 ± 1.32/mm2 for control; P < 0.05), with the hASC-Ang1 group showing significantly higher arteriole density compared to hASC.

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