Microenvironment drives the endothelial or neural fate of differentiating embryonic stem cells coexpressing neuropilin‐1 and Flk‐1

Gualandris, Anna; Noghero, Alessio; Geuna, Massimo; Arese, Marco; Valdembri, Donatella; Serini, Guido; Bussolino, Federico

doi:10.1096/fj.08-112847

Cited by 16 publications

(14 citation statements)

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“…We found hAFSCs to also express the selfrenewal (human embryonic) stem cell marker nodal (Besser, 2004) (Figure 3). We observed EB formation of hAFSCs to be accompanied by a decrease of nodal and Oct-4 expression and by induction of the differentiation markers Pax 6 (ectodermal), Flk1 (endothelial), Ecadherin (epithelial), GATA4 (endodermal), T (brachyury; mesodermal) and HBE1 (mesodermal) (Figure 3), which is in agreement with the observations on EB formation of embryonic stem cells (Narita et al, 1996;Itskovitz-Eldor et al, 2000;Yamashita et al, 2000;Besser, 2004;Ng et al, 2005;Koike et al, 2007;Kurosawa, 2007;Gualandris et al, 2008;Kim et al, 2008;Lim et al, 2008;Ungrin et al, 2008).…”

Section: Marker Expression In Ebs Derived From Hafscssupporting

confidence: 90%

Embryoid body formation of human amniotic fluid stem cells depends on mTOR

et al. 2009

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Human amniotic fluid stem cells (hAFSCs) harbor high proliferative capacity and high differentiation potential and do not raise the ethical concerns associated with human embryonic stem cells. The formation of threedimensional aggregates known as embryoid bodies (EBs) is the principal step in the differentiation of pluripotent embryonic stem cells. Using c-Kit-positive hAFSC lines, we show here that these stem cells harbor the potential to form EBs. As part of the two kinase complexes, mTORC1 and mTORC2, mammalian target of rapamycin (mTOR) is the key component of an important signaling pathway, which is involved in the regulation of cell proliferation, growth, tumor development and differentiation. Blocking intracellular mTOR activity through the inhibitor rapamycin or through specific small interfering RNA approaches revealed hAFSC EB formation to depend on mTORC1 and mTORC2. These findings demonstrate hAFSCs to be a new and powerful biological system to recapitulate the three-dimensional and tissue level contexts of in vivo development and identify the mTOR pathway to be essential for this process.

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Section: Marker Expression In Ebs Derived From Hafscssupporting

confidence: 90%

Embryoid body formation of human amniotic fluid stem cells depends on mTOR

et al. 2009

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“…Moreover, murine neural stem cells can engraft into the hematopoietic system of irradiated hosts to produce blood (Bjornson et al, 1999) while in the quail-chick chimera model the avian cranial neuroectoderm originates smooth muscle cells (Korn et al, 2002). In addition, embryonic stem cell-derived Neuropilin-1 positive cell population differentiates in vitro towards endothelial or neural phenotypes depending upon microenvironmental cues (Gualandris et al, 2009;Noghero et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Nervous vascular parallels: axon guidance and beyond

Arese¹,

Serini

Bussolino

2011

Int. J. Dev. Biol.

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The vascular and nervous systems are organized with well defined and accurate networks, which represent the anatomical structure enabling their functions. In recent years, it has been clearly demonstrated that these two systems share in common several mechanisms and specificities. For instance, the networking properties of the nervous and vascular systems are governed by common cues that in the brain regulate axon connections and in the vasculature remodel the primitive plexus towards the vascular tree. Here, we summarize the role of semaphorins as a paradigmatic example of the role of axon guidance molecules in physiological and pathological angiogenesis. Finally, we discuss the presence in blood vessels of neurexin and neuroligin, two proteins that finely modulate synaptic activity in the brain. This observation is suggestive of an intriguing new class of molecular and functional parallels between neurons and vascular cells.

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“…Initially, it was described as a regulator of axon collapse and enhancer of angiogenesis. Subsequently, new functions of NRP-1 were characterized and the expanded contemporary view of NRP-1 includes among its functions antigen recognition (3), adhesion via interaction with ␤ integrins (4,5), activation of latent forms of cytokines (6), control of stem cell differentiation (7)(8)(9), and viral infection (10).…”

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confidence: 99%

Exogenous Recombinant Dimeric Neuropilin-1 Is Sufficient to Drive Angiogenesis

Uniewicz

Fernig

2011

Journal of Biological Chemistry

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Neuropilin-1 (NRP-1) is present on the cell surface of endothelial cells, or as a soluble truncated variant. Membrane NRP-1 is proposed to enhance angiogenesis by promoting the formation of a signaling complex between vascular endothelial growth factor-A 165 (VEGF-A 165 ), VEGF receptor-2 (VEGFR-2) and heparan sulfate, whereas the soluble NRP-1 is thought to act as an antagonist of signaling complex formation. We have analyzed the angiogenic potential of a chimera comprising the entire extracellular NRP-1 region dimerized through an Fc IgG domain and a monomeric truncated NRP-1 variant. Both NRP-1 proteins stimulated tubular morphogenesis and cell migration in HDMECs and HUVECs. Fc rNRP-1 was able to induce VEGFR-2 phosphorylation and expression of the VEGFR-2 specific target, regulator of calcineurin-1 (RCAN1.4). siRNA mediated gene silencing of VEGFR-2 revealed that VEGFR-2 was required for Fc rNRP-1 mediated activation of the intracellular signaling proteins PLC-␥, AKT, and MAPK and tubular morphogenesis. The stimulatory activity was independent of VEGF-A 165 . This was evidenced by depleting the cell culture of exogenous VEGF-A 165 , and using instead for routine culture VEGF-A 121 , which does not interact with NRP-1, and by the inability of VEGF-A sequestering antibodies to inhibit the angiogenic activity of the NRP proteins. Analysis of angiogenesis over a period of 6 days in an in vitro fibroblast/endothelial co-culture model revealed that Fc rNRP-1 could induce endothelial cell tubular morphogenesis. Thus, we conclude that soluble Fc rNRP-1 is a VEGF-A 165 -independent agonist of VEGFR-2 and stimulates angiogenesis in endothelial cells. Neuropilin-1 (NRP-1)4 is a protein known for playing important functions in neural and vascular systems (reviewed in Refs. 1, 2). Initially, it was described as a regulator of axon collapse and enhancer of angiogenesis. Subsequently, new functions of NRP-1 were characterized and the expanded contemporary view of NRP-1 includes among its functions antigen recognition (3), adhesion via interaction with ␤ integrins (4, 5), activation of latent forms of cytokines (6), control of stem cell differentiation (7-9), and viral infection (10).The majority of studies analyzing NRP-1 function in endothelial cells have focused on the role of the native transmembrane protein. NRP-1 was shown to be abundantly expressed in human, mouse, and chick with highest expression in the vascular endothelium, heart and placenta (11-13). Moreover, it was shown that a homozygous deletion of the Nrp1 gene in mice causes embryonic lethality, because of defects in the vessels and general vascularization (14), while exogenously overexpressed NRP-1 led to formation of excess capillaries and hemorrhages (11).Overexpression of NRP-1 has been observed in the tumor microenvironment, where apart from endothelial cells, the tumor cells themselves were shown to express NRP-1 (15, 16). Current knowledge of NRP-1 places it among the key drivers of angiogenesis (17); however, it must be emphasized that the exact me...

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Microenvironment drives the endothelial or neural fate of differentiating embryonic stem cells coexpressing neuropilin‐1 and Flk‐1

Cited by 16 publications

References 50 publications

Embryoid body formation of human amniotic fluid stem cells depends on mTOR

Embryoid body formation of human amniotic fluid stem cells depends on mTOR

Nervous vascular parallels: axon guidance and beyond

Exogenous Recombinant Dimeric Neuropilin-1 Is Sufficient to Drive Angiogenesis

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