Embryonic Stem Cells: A Novel Tool for the Study of Antiangiogenesis and Tumor-Induced Angiogenesis

Wartenberg, Maria; Dönmez, Fatma; Budde, Paula; Sauer, Heinrich

doi:10.1007/3-540-31265-x_3

Cited by 4 publications

(1 citation statement)

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“…NO has been shown to be a prerequisite for blood vessel formation during stem cell differentiation [23], whereas STAT3 regulates expression of AKT, which is required for growth signal-induced HIF-1 upregulation [24]. ES cells can be differentiated to three-dimensional tissues in which effective vasculogenesis and angiogenesis occurs, thus allowing to study the effects of pro-angiogenic and anti-angiogenic compounds on blood vessel formation and the underlying signaling cascades [25]. Since stem cells are involved in regenerative processes, and neo-angiogenesis is a central feature during regeneration and repair following tissue injury, the results of the present study will add to the understanding of the organ-protective effect of this milk thistle compound.…”

Section: Silibinin From Silybum Marianum Stimulates Embryonic Stem Cell Vascular Differentiation Via the Stat3/pi3-k/akt Axis And Nitric mentioning

confidence: 99%

Silibinin from Silybum marianum Stimulates Embryonic Stem Cell Vascular Differentiation via the STAT3/PI3-K/AKT Axis and Nitric Oxide

et al. 2018

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Silibinin, the bioactive compound of milk thistle (), exerts tissue protective and regenerative effects that may include stem cell differentiation toward vascular cells. The purpose of the present study was to investigate whether silibinin stimulates blood vessel formation from mouse embryonic stem (ES) cells and to unravel the underlying signaling cascade. Vascular branching points were assessed by confocal laser scanning microscopy and computer-assisted image analysis of CD31-positive cell structures. Protein expression of vascular markers and activation of protein kinases were determined by western blot. Nitric oxide (NO) generation was investigated by use of the fluorescent dye 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate. Silibinin dose-dependently increased CD31-positive vascular branching points in embryoid bodies cultivated from ES cells. This was paralleled by increase of protein expression levels for the endothelial-specific markers vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor receptor 2, and hypoxia-inducible factor-1α. Moreover, silibinin increased activation of endothelial nitric oxide synthase (eNOS), which boosted generation of NO in embryoid bodies and enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) as well as phosphoinositide 3-kinase (PI3-K) and AKT. Vasculogenesis, VE-cadherin expression, STAT3 and AKT phosphorylation, NO generation, and eNOS phosphorylation were inhibited by the small molecule STAT3 inhibitor Stattic, AKT inhibitor VIII, the PI3-K inhibitor LY294002, or the NOS inhibitor N-Nitro-L-arginine methyl ester hydrochloride. In conclusion, our findings indicate that silibinin induces vasculogenesis of ES cells via activation of STAT3, PI3-K, and AKT, which regulate NO generation by eNOS.

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Section: Silibinin From Silybum Marianum Stimulates Embryonic Stem Cell Vascular Differentiation Via the Stat3/pi3-k/akt Axis And Nitric mentioning

confidence: 99%

Silibinin from Silybum marianum Stimulates Embryonic Stem Cell Vascular Differentiation via the STAT3/PI3-K/AKT Axis and Nitric Oxide

et al. 2018

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Models for Angiogenesis

Kassis

Cohen

Rasool

et al. 2007

The Cancer Handbook

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The study of angiogenesis has produced a plethora of creative assays through which various aspects of vascular formation and growth are observed, measured, evaluated, and inhibited. A basic theme of angiogenesis investigation is that multiple models are needed to prove a hypothesis. Thus, different aspects are tested in separate models in order to circumscribe those selected effects on the vasculature. Traditional models of the study of angiogenesis have generally been categorized into either in vitro or in vivo assays. In vitro models allow for more strict control over the local microenvironment, sometimes at the expense of authenticity to the in vivo event, whereas in vivo models enable more accurate observations in a simulated live environment at the expense of optimizing certain variables. A balance of various techniques involving both in vitro and in vivo models has led to a better understanding of the overall process of angiogenesis, and thus enabled the development of more effective targeting and therapeutic agents.

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