Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction

Locatelli, Paola; Olea, Fernanda Daniela; Hnatiuk, Anna P.; Lorenzi, Andrea; Cerdá, Miguel; Giménez, Carlos Sebastián; Sepulveda, Diana E.; Laguens, Rubén M.; Crottogini, Alberto J.

doi:10.1038/gt.2015.28

Cited by 29 publications

(18 citation statements)

References 46 publications

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“…VEGF has been used as a potent therapeutic reagent in the treatment of ischemia via the induction of angiogenesis in MSCs. VEGF-modified MSCs have been shown to possess an enhanced repair capacity due to the induction of angiogenesis and an enhanced paracrine effect (7,18–21). Of note, the expression of VEGF in MSCs has been shown to be upregulated by Bcl-2 modification under hypoxic conditions (8).…”

Section: Discussionmentioning

confidence: 99%

Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro

Guo

et al. 2017

International Journal of Molecular Medicine

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Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for ischemic heart disease; however, the low survival rate of transplanted cells limits their therapeutic efficacy. The aim of this study was to investigate whether the dual genetic modification of vascular endothelial growth factor (VEGF) and B-cell lymphoma-2 (Bcl-2) confers a higher expression level of the target genes, better survival and a stronger paracrine effect in MSCs in an adverse environment than the modification of the individual genes. For this purpse, a lentiviral vector was constructed by using a self-cleaving T2A peptide sequence to link and achieve the co-overexpression of VEGF and Bcl-2. Rat MSCs were transfected to obtain cell lines that exhibited a stable overexpression. An in vitro model of oxygen glucose deprivation (OGD) was applied to mimic the ischemic microenvironment, and cell apoptosis, autophagy and the paracrine effects were then determined. Compared with the MSCs in which individual genes were modified and the control MSCs, the MSCs which were subjected to dual genetic modification had a higher expression level of the target genes, a more rapid proliferation, reduced apoptosis, decreased autophagy and an enhanced paracrine effect. Furthermore, the suppression of autophagy was found to contribute to the inhibition of apoptosis in this in vitro OGD model. On the whole, these data indicate that the co-overexpression of VEGF and Bcl-2 protects MSCs in an ischemic environment by inhibiting apoptosis, suppressing autophagy and enhancing the paracrine effects.

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Section: Discussionmentioning

confidence: 99%

Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro

Guo

et al. 2017

International Journal of Molecular Medicine

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“…In terms of neovascularization, both BMMSC and BMMSC‐HIF increased arteriolar density at 7 and 60 days post‐treatment, with a significantly larger degree in the latter. Given that BMMSCs secrete a number of paracrine molecules involved in migration and proliferation of vascular smooth‐muscle cells, enhanced arteriolar growth in animals receiving BMMSC was expected . The fact that this effect was stronger in BMMSC‐HIF treated sheep can be attributed to HIF‐mediated overexpression of angiogenic genes as well as enhanced cell retention, as indicated by our long‐term tracking experiments.…”

Section: Discussionmentioning

confidence: 55%

“…Given that BMMSCs secrete a number of paracrine molecules involved in migration and proliferation of vascular smoothmuscle cells, enhanced arteriolar growth in animals receiving BMMSC was expected. [21][22][23][24] The fact that this effect was stronger in BMMSC-HIF treated sheep can be attributed to HIF-mediated overexpression of angiogenic genes as well as enhanced cell retention, as indicated by our long-term tracking experiments. Capillary density was also maximal in BMMSC-HIF at both time points.…”

Section: Discussionmentioning

confidence: 55%

“…32 We also observed that VEGF-transfected BMMSCs injected into the peri-infarct of ovine myocardium, while abundant at 7 days, were very scarce 1 month after delivery. 24 In this study, we demonstrate a higher percentage of retained postinjection cells at day 1, which may be explained by the implementation of injection technique and also by the immunomodulatory characteristic of the BMMSCs, which may reduce the immune response preventing cell death.…”

Section: Discussionmentioning

confidence: 58%

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Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

Hnatiuk

Ong

Olea

et al. 2016

JAHA

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BackgroundBone marrow mesenchymal stromal cells (BMMSCs) are cardioprotective in acute myocardial infarction (AMI) because of release of paracrine angiogenic and prosurvival factors. Hypoxia‐inducible factor 1‐α (HIF1‐α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSCs engineered to overexpress mutant, oxygen‐resistant HIF1‐α would confer greater cardioprotection than nontransfected BMMSCs in sheep with AMI.Methods and ResultsAllogeneic BMMSCs transfected with a minicircle vector encoding mutant HIF1‐α (BMMSC‐HIF) were injected in the peri‐infarct of sheep (n=6) undergoing coronary occlusion. Over 2 months, infarct volume measured by cardiac magnetic resonance (CMR) imaging decreased by 71.7±1.3% (P<0.001), and left ventricular (LV) percent ejection fraction (%EF) increased near 2‐fold (P<0.001) in the presence of markedly decreased end‐systolic volume. Sheep receiving nontransfected BMMSCs (BMMSC; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo‐treated animals (n=6), neither parameters changed over time. HIF1‐α‐transfected BMMSCs (BMMSC‐HIF) induced angio‐/arteriogenesis and decreased apoptosis by HIF1‐mediated overexpression of erythropoietin, inducible nitrous oxide synthase, vascular endothelial growth factor, and angiopoietin‐1. Cell tracking using paramagnetic iron nanoparticles in 12 additional sheep revealed enhanced long‐term retention of BMMSC‐HIF.ConclusionsIntramyocardial delivery of BMMSC‐HIF reduced infarct size and improved LV systolic performance compared to BMMSC, attributed to increased neovascularization and cardioprotective effects induced by HIF1‐mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSCs for allogeneic application, this treatment may be potentially useful in the clinic.

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“…Aiming at a clear indication of which factors could account for the human umbilical cord tissue‐derived MSCs‐mediated beneficial effects in MI murine model, it is concluded that the expression of angiogenesis‐associated transcripts (subtypes of VEGF, Angs, HGF, C‐met, bFGF, transforming growth factor beta, and platelet‐derived growth factor alpha polypeptide β) is high . Recently, Locatelli et al found that MSCs overexpressing VEGF165 (MSCs‐pVEGF) would afford greater cardioprotection than nonmodified MSCs or pVEGF alone. In the current study, the better effects shown in the CD34+ cells‐treated group than the MSCs‐treated group may be attributed to the intrinsic differential expression of the proangiogenic factors as we found that there were upregulation of both human VEGF and human hif‐1α in the infarcted hearts treated by CD34+ cells than that treated by MSCs.…”

Section: Discussionmentioning

confidence: 99%

Comparing the effects of MSCs and CD34+ cell therapy in a rat model of myocardial infarction

et al. 2016

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Stem cell therapy is considered as a promising approach in the treatment of myocardial infarction (MI). This study was designed as a comparison of human umbilical cord blood (HUCB)-derived CD341 and HUCB-derived MSCs for the repair of cardiac tissue by induction of the angiogenesis. Forty-eight male rats were randomized into four groups: sham-operated group, MI group, MSCs-treated group, and CD341 cellstreated group. After 4 weeks, the rats were sacrificed. All sections from left ventricles of all groups were subjected to hematoxylin & eosin, Masson's trichrome, and immunohistochemical stains (CD133, CD44, and a-smooth muscle actin). RNA was extracted for gene expression of the angiogenic markers. A significant reduction of the infarct size and the amplitude of T-wave in the CD341 cells-treated group when compared with the MSCs-treated group were determined. Histologically, the MI group showed scar tissue, congested blood capillaries around the infarcted area, some necrotic cells, and inflammatory cells. Administration of either MSCs or CD341 cells had a therapeutic potential to induce regenerative changes in the myocardium with better results in CD341cells-treated group. Quantitative RT-PCR analysis revealed a significant increase in the expression of vascular endothelial growth factor (VEGF), VEGFR-2, Ang-1, and Tie-2 and a significant decreased expression of Ang-2 in stem cells transplanted groups when compared with the noncell transplanted hearts. A significant increase of VEGF, VEGFR-2, Ang-1, and Tie-2 expression in the group receiving CD341 cells than those receiving MSCs was found. Finally, there was an upregulation of both human VEGF and human hypoxia-inducible factor 1a in the infarcted hearts treated by CD341 cells than that treated by MSCs. We first revealed a superior efficacy of CD341 cells when compared with MSCs in induction of regenerative changes in the MI model. Both cell therapies may repair the damaged heart tissue primarily by secretion of proangiogenic factors that induce the angiogenesis and activate the angiogenesis signaling pathway. V C 2016 IUBMB Life, 68(5): [343][344][345][346][347][348][349][350][351][352][353][354] 2016

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Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction

Cited by 29 publications

References 46 publications

Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro

Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro

Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

Comparing the effects of MSCs and CD34+ cell therapy in a rat model of myocardial infarction

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