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A Review of Vasculogenesis Models  [PDF]
D. Ambrosi,F. Bussolino,L. Preziosi
Computational and Mathematical Methods in Medicine , 2005, DOI: 10.1080/1027366042000327098
Abstract: Mechanical and chemical models of vasculogenesis are critically reviewed with an emphasis on their ability to predict experimentally measured quantities. Final remarks suggest a possibility to merge the capabilities of different models into a unified approach.
Vasculogenesis in rheumatoid arthritis
Zoltán Szekanecz, Alisa E Koch
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2943
Abstract: Endothelial progenitor cells (EPCs) are hematopoietic stem cells expressing CD34, CD133, type 2 vascular endothelial growth factor (VEGF) receptor (VEGFR-2 or Flk-1), and the CXCR4 chemokine receptor [1-4]. During vasculogenesis, EPCs are mobilized from the bone marrow and they differentiate into mature endothelial cells [3]. Under normal conditions, vasculogenesis is involved in both prenatal and postnatal tissue development, vascular repair, and atherosclerosis [2,3].In rheumatoid arthritis (RA), several groups have described defective vasculogenesis related to impaired EPC numbers and functions in RA [4-6]. Impaired vasculogenesis has been associated with increased cardiovascular morbidity and mortality in RA [7,8]. Effective antirheumatic therapy, such as corticosteroids and tumor necrosis factor-alpha (TNF-α) blockers, may stimulate the outgrowth and function of EPCs and thus may restore defective vasculogenesis in arthritis [5]. In addition, as the induction of vasculogenesis may be beneficial for patients with cardiovascular disease [8], the stimulation of EPCs and vasculogenesis may also suppress premature atherosclerosis underlying RA [7].In the previous issue of Arthritis Research & Therapy, Jodon de Villeroché and colleagues [1] assessed late-outgrowth EPCs in RA and found increased colony-formation capacity of these cells in RA. Furthermore, higher or lower EPC numbers correlated with active disease and disease in remission, respectively. These results seem to be somewhat controversial as a number of other investigators reported defective EPC function in RA and lower EPC numbers in active RA [5,6]. There has been only one report by the same group, Allanore and colleagues [9], suggesting that circulating EPC numbers may be higher in RA. Nevertheless, Jodon de Villeroché and colleagues [1] conducted an approach that was significantly different from that of others. Instead of analyzing all EPCs, they differentiated two EPC sub-populations, namely EPCs of mo
In vivo consequences of deleting EGF repeats 8–12 including the ligand binding domain of mouse Notch1
Changhui Ge, Tongyi Liu, Xinghua Hou, Pamela Stanley
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-48
Abstract: Notch1lbd/lbd embryos died at mid-gestation with a phenotype indistinguishable from Notch1 null mutants. In embryonic stem (ES) cells, Notch1lbd was expressed on the cell surface at levels equivalent to wild type Notch1, but Delta1 binding was reduced to the same level as in Notch1 null cells. In an ES cell co-culture assay, Notch signaling induced by Jagged1 or Delta1 was reduced to a similar level in Notch1lbdand Notch1 null cells. However, the Notch1lbd/lbd allele was expressed similarly to wild type Notch1 in Notch1lbd/lbd ES cells and embryos at E8.75, indicating that Notch1 signaling is not essential for the Notch1 gene to be expressed. In addition, maternal and zygotic Notch1 mutant blastocysts developed through gastrulation.Mouse Notch1 lacking the ligand binding domain is expressed at the cell surface but does not signal in response to the canonical Notch ligands Delta1 and Jagged1. Homozygous Notch1lbd/lbd mutant embryos die at ~E10 similar to Notch1 null embryos. While Notch1 is expressed in oocytes and blastocysts, Notch1 signaling via canonical ligands is dispensable during oogenesis, blastogenesis, implantation and gastrulation.Notch1 is a heterodimeric, type I transmembrane receptor that is required for cell fate decisions throughout the metazoa [1,2]. The Notch1 extracellular domain contains 36 tandem epidermal growth factor-like (EGF) repeats, and three Lin/Notch repeats. Of the 36 EGF repeats in Drosophila Notch, deletion of only EGF repeats 11 and 12 prohibits the binding of the Notch ligands Delta and Serrate in in vitro binding assays [3,4]. Notch signaling in mammals is also initiated by binding to canonical Notch ligands (Delta and Jagged) on adjacent cells. Ligand binding activates Notch signaling through two proteolytic cleavage events, first in the extracellular domain by the ADAM10 metalloprotease [5], and subsequently in the transmembrane domain by a presenilin complex with γ-secretase activity [6,7]. The released Notch intracellular doma
cGMP-Dependent Protein Kinase I Is Crucial for Angiogenesis and Postnatal Vasculogenesis  [PDF]
Alexandra Aicher, Christopher Heeschen, Susanne Feil, Franz Hofmann, Michael E. Mendelsohn, Robert Feil, Stefanie Dimmeler
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004879
Abstract: Background Endothelium-derived nitric oxide plays an important role for the bone marrow microenvironment. Since several important effects of nitric oxide are mediated by cGMP-dependent pathways, we investigated the role of the cGMP downstream effector cGMP-dependent protein kinase I (cGKI) on postnatal neovascularization. Methodology/Principal Findings In a disc neovascularization model, cGKI?/? mice showed an impaired neovascularization as compared to their wild-type (WT) littermates. Infusion of WT, but not cGKI?/? bone marrow progenitors rescued the impaired ingrowth of new vessels in cGKI-deficient mice. Bone marrow progenitors from cGKI?/? mice showed reduced proliferation and survival rates. In addition, we used cGKIα leucine zipper mutant (LZM) mice as model for cGKI deficiency. LZM mice harbor a mutation in the cGKIα leucine zipper that prevents interaction with downstream signaling molecules. Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice. Conclusions/Significance Our findings demonstrate that the cGMP-cGKI pathway is critical for postnatal neovascularization and establish a new role for cGKI in vasculogenesis, which is mediated by bone marrow-derived progenitors.
NOTCH1 Gain of Function in Germ Cells Causes Failure of Spermatogenesis in Male Mice  [PDF]
Zaohua Huang, Bryan Rivas, Alexander I. Agoulnik
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071213
Abstract: NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans-membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icre transgene we produced mice with conditional activation of the NOTCH1 intracellular domain (NICD) in germ cells. Spermatogenesis in these mutants was progressively affected with age, resulting in decreased testis weight and sperm count. Analysis of downstream target genes of NOTCH1 signaling showed an increased expression of Hes5, with a reduction of the spermatogonial differentiation marker, Neurog3 expression in the mutant testis. Apoptosis was significantly increased in mouse germ cells with the corresponding elevation of pro-apoptotic Trp53 and Trp63 genes' expression. We also showed that the conditional germ cell-specific ablation of Notch1 had no effect on spermatogenesis or male fertility. Our data suggest the importance of NOTCH signaling regulation in male germ cells for their survival and differentiation.
Therapeutic promise and challenges of targeting DLL4/NOTCH1
Minhong Yan
Vascular Cell , 2011, DOI: 10.1186/2045-824x-3-17
Abstract: In metazoans, the evolutionarily conserved NOTCH pathway functions as an essential mechanism to regulate numerous cell fate/lineage decisions during embryogenesis, postnatal development, and in the maintenance of adult tissue homeostasis. NOTCH receptors are normally constrained in a dormant state. Ligand binding exposes the ADAM protease cleavage site that is normally buried within the negative regulatory region (NRR)[1]. Subsequent intramembrane cleavage catalyzed by γ-secretase, a multisubunit protein complex, permits the release of the intracellular portion (NICD) from the cell membrane and its entry into the nucleus where it forms a transcriptional activation complex. In mammals, the NOTCH signaling apparatus consists of four single-pass transmembrane receptors (NOTCH1-4) and at least five membrane-anchored ligands (Jagged1, 2 and Delta-like or DLL1, 3 and 4). Despite the apparent redundancy of multiple NOTCH ligands and receptors expressed in the vascular system, recent studies have revealed that the DLL4-NOTCH 1 interaction appears to be the dominant functioning component in the vascular system. DLL4 was initially identified as an endothelium-specific NOTCH ligand [2-5]. Haploinsufficiency of Dll4 in mice results in early embryonic lethality due to severe vascular defects including impaired arteriogenesis, disrupted vascular hierarchy, and enhanced vascular density with reduced vessel caliber [2,6,7]. This uniquely non-redundant role of DLL4 goes beyond early embryonic development. Studies utilizing a DLL4-selective antagonistic antibody demonstrate that DLL4 is also essential for early postnatal vascular development, angiogenesis during pathological wound healing (unpublished observations) and tumor angiogenesis [8]. Compared to DLL4, NOTCH1 is more broadly expressed and targeted disruption of Notch1 results in vascular defects similar to what has been observed with Dll4 deficiency [9,10]. Moreover, results from recent work using paralogue-specific antibodie
Involvement of Notch1 inhibition in serum-stimulated glia and oligodendrocyte differentiation from human mesenchymal stem cells  [cached]
Yi-Jang Lee,Shih-Chieh Hung,Mien-Sheng Chu
Stem Cells and Cloning: Advances and Applications , 2010,
Abstract: Yi-Jang Lee1, Shih-Chieh Hung2–5, Mien-Sheng Chu41Department of Biomedical Imaging and Radiological Sciences, 2Institute of Clinical Medicine, 3Institute of Pharmacology, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 4Stem Cell Laboratory, Department of Medical Research and Education, 5Department of Orthopedics, Taipei Veterans General Hospital, Taipei 112, TaiwanAbstract: The use of in vitro oligodendrocyte differentiation for transplantation of stem cells to treat demyelinating diseases is an important consideration. In this study, we investigated the effects of serum on glia and oligodendrocyte differentiation from human mesenchymal stem cells (KP-hMSCs). We found that serum deprivation resulted in a reversible downregulation of glial- and oligodendrocyte-specific markers. Serum stimulated expression of oligodendrocyte markers, such as galactocerebroside, as well as Notch1 and JAK1 transcripts. Inhibition of Notch1 activation by the Notch inhibitor, MG132, led to enhanced expression of a serum-stimulated oligodendrocyte marker. This marker was undetectable in serum-deprived KP-hMSCs treated with MG132, suggesting that inhibition of Notch1 function is additive to serum-stimulated oligodendrocyte differentiation. Furthermore, a dominant-negative mutant RBP-J protein also inhibited Notch1 function and led to upregulation of oligodendrocyte-specific markers. Our results demonstrate that serum-stimulated oligodendrocyte differentiation is enhanced by the inhibition of Notch1-associated functions.Keywords: mesenchymal stem cells, glia and oligodendrocyte differentiation, Notch1 signaling, serum deprivation
Inhibition of Fibroblast Growth by Notch1 Signaling Is Mediated by Induction of Wnt11-Dependent WISP-1  [PDF]
Zhao-Jun Liu, Yan Li, Yurong Tan, Min Xiao, Jialin Zhang, Freddy Radtke, Omaida C. Velazquez
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038811
Abstract: Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM). They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1Flox/Flox) embryonic fibroblasts (MEFs). Notch1-deficient (Notch1?/?) MEFs displayed faster growth and motility rate compared to Notch1Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1) in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441), which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1). Functionally, “Notch-activated” stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4) in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.
Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis  [cached]
Kelley M Argraves,Brent A Wilkerson,W Scott Argraves
World Journal of Biological Chemistry , 2010,
Abstract: Blood vessels either form de novo through the process of vasculogenesis or through angiogenesis that involves the sprouting and proliferation of endothelial cells in pre-existing blood vessels. A complex interactive network of signaling cascades downstream from at least three of the nine known G-protein-coupled sphingosine-1-phosphate (S1P) receptors act as a prime effector of neovascularization that occurs in embryonic development and in association with various pathologies. This review focuses on the current knowledge of the roles of S1P signaling in vasculogenesis and angiogenesis, with particular emphasis on vascular cell adhesion and motility responses.
Involvement of Notch1 inhibition in serum-stimulated glia and oligodendrocyte differentiation from human mesenchymal stem cells
Yi-Jang Lee, Shih-Chieh Hung, Mien-Sheng Chu
Stem Cells and Cloning: Advances and Applications , 2010, DOI: http://dx.doi.org/10.2147/SCCAA.S14388
Abstract: volvement of Notch1 inhibition in serum-stimulated glia and oligodendrocyte differentiation from human mesenchymal stem cells Original Research (2539) Total Article Views Authors: Yi-Jang Lee, Shih-Chieh Hung, Mien-Sheng Chu Published Date November 2010 Volume 2010:3 Pages 165 - 173 DOI: http://dx.doi.org/10.2147/SCCAA.S14388 Yi-Jang Lee1, Shih-Chieh Hung2–5, Mien-Sheng Chu4 1Department of Biomedical Imaging and Radiological Sciences, 2Institute of Clinical Medicine, 3Institute of Pharmacology, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 4Stem Cell Laboratory, Department of Medical Research and Education, 5Department of Orthopedics, Taipei Veterans General Hospital, Taipei 112, Taiwan Abstract: The use of in vitro oligodendrocyte differentiation for transplantation of stem cells to treat demyelinating diseases is an important consideration. In this study, we investigated the effects of serum on glia and oligodendrocyte differentiation from human mesenchymal stem cells (KP-hMSCs). We found that serum deprivation resulted in a reversible downregulation of glial- and oligodendrocyte-specific markers. Serum stimulated expression of oligodendrocyte markers, such as galactocerebroside, as well as Notch1 and JAK1 transcripts. Inhibition of Notch1 activation by the Notch inhibitor, MG132, led to enhanced expression of a serum-stimulated oligodendrocyte marker. This marker was undetectable in serum-deprived KP-hMSCs treated with MG132, suggesting that inhibition of Notch1 function is additive to serum-stimulated oligodendrocyte differentiation. Furthermore, a dominant-negative mutant RBP-J protein also inhibited Notch1 function and led to upregulation of oligodendrocyte-specific markers. Our results demonstrate that serum-stimulated oligodendrocyte differentiation is enhanced by the inhibition of Notch1-associated functions.
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