VEGF promotes cardiac stem cells differentiation into vascular endothelial cells via the PI3K/Akt signaling pathway

Xiao, Na; Qi, Xiaoyong; Tang, Lu-Ning; Tan, Lu; Chang, Yaqing; Zhao, Hongmei

doi:10.3109/21691401.2013.837473

Cited by 17 publications

(12 citation statements)

References 22 publications

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“…In a previous study, BM-MSCs were treated with VEGF under hypoxic conditions, and a greater proportion of BM-MSCs differentiated into endothelial cells when compared with those cultured under standard conditions (8). Xiao et al (22) demonstrated that PI3K/AKT signaling pathway served an important role in rat cardiac stem cell differentiation into endothelial cells, while Wortmannin (a PI3K/AKT signaling pathway inhibitor) was able to decrease this differentiation. Other than its role in promoting differentiation towards endothelial cells, the PI3K/AKT pathway has been shown to participate in improving neovascularization of human umbilical vein endothelial cells, and LY294002 has been demonstrated to abolish this positive effect (32).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, qPCR was used to measure the gene expression of VEGF, which is the most important angiogenesis-associated cytokine (22). Following appropriate treatment for 7 days, 1×10 6 cells were collected from each group, and total RNA was prepared from the cells using TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

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Effect of the PI3K/AKT signaling pathway on hypoxia-induced proliferation and differentiation of bone marrow-derived mesenchymal stem cells

Sheng

Mao

et al. 2016

Experimental and Therapeutic Medicine

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Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has been demonstrated to be an effective way of augmenting angiogenesis of ischemic tissue. The low oxygen conditions in ischemic tissue directly affect the biological behavior of engrafted cells. However, to date, the mechanism through which hypoxia regulates self-renewal, differentiation and paracrine function of BM-MSCs remains unclear. Clarification of this mechanism would be beneficial to the use of stem cell-based therapy. The PI3K/AKT pathway has been extensively investigated for its role in cell proliferation, cell transformation, paracrine function and angiogenesis. The present study aimed to analyze the role of PI3K/AKT pathway in hypoxia-induced proliferation of BM-MSCs and their differentiation into endothelial cells in vitro by the application of LY294002, a PI3K/AKT pathway inhibitor, with cells cultured in normoxia serving as a control. The results showed that rat BM-MSCs at passage 3 and 4 displayed only few phenotypical differences in the expression of surface antigens as detected by flow cytometry. When compared with the cells treated in normoxia, the proliferation of BM-MSCs in hypoxia was promoted, a greater number of cells expressed CD31 and a higher expression of vascular endothelial growth factor was observed after culture in hypoxic conditions. However, by inhibiting with LY294002, these changes induced by hypoxia were partly inhibited. In conclusion, the present study showed that the PI3K/AKT pathway served an important role in hypoxia-enhanced in vitro proliferation of BM-MSCs and their differentiation into endothelial cells and paracrine vascular endothelial growth factor.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effect of the PI3K/AKT signaling pathway on hypoxia-induced proliferation and differentiation of bone marrow-derived mesenchymal stem cells

Sheng

Mao

et al. 2016

Experimental and Therapeutic Medicine

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“… 114 Preclinical animal studies demonstrated that VEGF-A 165 gene therapy resulted in the induction of angiogenesis, arteriogenesis, and vasculogenesis, 92 , 93 recovery of ventricular function during ischaemia, reduction in apoptosis of the infarcted area. 94 VEGF also plays a role in the recruitment and homing of cardiac and endothelial progenitor cells 115 and maintenance of physiological homeostasis in the heart. 116 Translational studies in large animal models confirmed some of the beneficial effects of VEGF, either by itself or in combination with other angiogeneic factors (e.g.…”

Section: Therapeutic Genes For Gene Therapy For Cvdmentioning

confidence: 99%

Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation

2015

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Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca2+-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality.

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“…VEGF binding stimulated proliferation and decreased apoptosis of endothelial cells, leading to the increased efficiency of ischemic hindlimb treatment. In addition, VEGF prevents apoptosis through phosphatidylinositol (PI)-3-kinase Akt pathway or through the stimulation of antiapoptosis Bcl-2 and A1 factors production in endothelial cells (Karar and Maity, 2011;Xiao et al, 2014). PI-3-kinase Akt pathway activates vascular growth factors such as eNOS and HIF-1α.…”

Section: Discussionmentioning

confidence: 99%

Human adipose-derived mesenchymal stem cell could participate in angiogenesis in a mouse model of acute hindlimb ischemia

Dao

Phi

et al. 2016

Biomed Res Ther

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Abstract-Introduction:Mesenchymal stem cells (MSCs) transplantation for the treatment of acute hindlimb ischemia is recently attracting the attention of many scientists. Identifying the role of donor cells in the host is a crucial factor for improving the efficiency of treatment. This study evaluated the injury repair role of xenogeneic adipose-derived stem cell (ADSC) transplantation in acute hindlimb ischemia mouse model. Methods: Human ADSCs were transplanted into the limb of ischemic mouse. The survival rate of grafted cells and expression of human VEGF-R2 and CD31 positive cells were assessed in the mouse. In addition, the morphological and functional recovery of ischemic hindlimb was also assessed. Results: The results showed that one-day post cell transplantation, the survival percentage of grafted cells was 3.62% ± 2.06% at the injection site and 15.71% ± 12.29% around the injection site. The rate of VEGFR2-positive cells had highest expression at 4 days post transplantation, 5.46% ± 2.13% at the injection site; 9.12% ± 7.17% at the opposite of injection site, and 7.22% ± 4.59% at the lateral gastrocnemius. The percentage of CD31 positive cells increased on day 4 at the injection site to 0.8% ± 1.60%, and further increased on day 8 at the lateral gastrocnemius site and the opposite injection site to 1.56% ± 0.44% and 1.17% ± 1.69%, respectively. After 14 days, the cell presentation and the angiogenesis marker expression were decreased to zero, except for CD31 expression at the opposite of injection site (0.72% ± 1.03%). Histological structure of the cell-injected muscle tissue remained stable as that of the normal muscle. New small blood vessels were found growing in hindlimb. On the other hand, approximately 66.67% of mice were fully recovered from ischemic hindlimb at grade 0 and I after cell injection. Conclusion: Thus, xenotransplantation of human ADSCs might play a significant role in the formation of new blood vessel and can assist in the treatment of mouse with acute hindlimb ischemia.

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VEGF promotes cardiac stem cells differentiation into vascular endothelial cells via the PI3K/Akt signaling pathway

Cited by 17 publications

References 22 publications

Effect of the PI3K/AKT signaling pathway on hypoxia-induced proliferation and differentiation of bone marrow-derived mesenchymal stem cells

Effect of the PI3K/AKT signaling pathway on hypoxia-induced proliferation and differentiation of bone marrow-derived mesenchymal stem cells

Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation

Human adipose-derived mesenchymal stem cell could participate in angiogenesis in a mouse model of acute hindlimb ischemia

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