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

Abstract

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 hASCAng1 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.

Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton’s jelly

“…Angiopoietin-1 is an important pro-angiogenic factor involved in vascular maturation and neovasculogenesis. Similar to what was described for VEGF, genetically modified MSC expressing angiopoietin-1 were more effective in regenerating myocardial tissue after infarction than MSC alone [ 39 ]. Liu and coworkers also demonstrated that MSC expressed functional receptors for angiopoietin-1 and that angiopoietin-1 protected MSC against apoptosis induced by hypoxia and serum deprivation [ 40 ].…”

Angiopoietin-1 Modified Human Umbilical Cord Mesenchymal Stem Cell Therapy for Endotoxin-Induced Acute Lung Injury in Rats

“…Angiopoietin-1 (Ang1) can significantly promote neovascularization via the inhibition of leukocyte-endothelium interactions and endothelial permeability,2 and during this course, vascular endothelial growth factor (VEGF) might be released from genetically modified adipose stem cells 7. Xu, et al8 reported that LPS-induced lung injury was alleviated in mice treated with BM-MSCs (from bone marrow, BM) carrying Ang1 (MSCs-Ang1), compared with mice treated with only MSCs or Ang1 in vivo .…”

Bioactive baculovirus nanohybrids for stent based rapid vascular re-endothelialization

“…The viral surface has been chemically modified to form cationic nanostructures, similar to our earlier studies232425, for local delivery of human vascular endothelial growth factor-A 165 (Vegf) therapeutic genes to attenuate ISR26. Insect cell host-specific baculovirus (Bac) offers a unique advantage over other gene delivery systems because of its ability to efficiently transduce non-dividing cells, inherent inability to replicate in mammalian cells, low cytotoxicity even at high viral dosage, absence of preexisting antibodies against Bac in animals and also easy production scale up to high viral titre2728.…”