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Yuan Xiao, Reza Riahi, Peter Torab, Donna D Zhang, Pak Kin Wong
Collective cell migration plays a pivotal role in development, wound healing, and metastasis, but little is known about the mechanisms and coordination of cell migration in 3D microenvironments. Here, we demonstrate a 3D wound healing assay by photothermal ablation for investigating collective cell migration in epithelial tissue structures. The nanoparticle-mediated photothermal technique creates local hyperthermia for selective cell ablation and induces collective cell migration of 3D tissue structures. By incorporating dynamic single cell gene expression analysis, live cell actin staining, and particle image velocimetry, we show that the wound healing response consists of 3D vortex motion moving toward the wound followed by the formation of multicellular actin bundles and leader cells with active actin-based protrusions...
February 13, 2019: ACS Nano
Pei-Suen Tsou, Phillip Campbell, M Asif Amin, Patrick Coit, Shaylynn Miller, David A Fox, Dinesh Khanna, Amr H Sawalha
Scleroderma (SSc) is a complex disease that involves activation of the immune system, vascular complications, and tissue fibrosis. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) mediates trimethylation of lysine 27 of histone 3 (H3K27me3), which acts as a repressive epigenetic mark. Both EZH2 and H3K27me3 were elevated in SSc dermal fibroblasts and endothelial cells compared with healthy controls. EZH2 inhibitor DZNep halted fibrosis both in vitro and in vivo. In SSc fibroblasts, DZNep dose-dependently reduced the expression of profibrotic genes and inhibited migratory activity of SSc fibroblasts...
February 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
Ornellie Bernadin, Fouzia Amirache, Anais Girard-Gagnepain, Ranjita Devi Moirangthem, Camille Lévy, Kuiying Ma, Caroline Costa, Didier Nègre, Christian Reimann, David Fenard, Agata Cieslak, Vahid Asnafi, Hanem Sadek, Rana Mhaidly, Marina Cavazzana, Chantal Lagresle-Peyrou, François-Loïc Cosset, Isabelle André, Els Verhoeyen
T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7-stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated by culture of CD34+ cells on Delta-like ligand 4 (Dll4)...
February 12, 2019: Blood Advances
Mattia Francesco Maria Gerli, Louise Anne Moyle, Sara Benedetti, Giulia Ferrari, Ekin Ucuncu, Martina Ragazzi, Chrystalla Constantinou, Irene Louca, Hiroshi Sakai, Pierpaolo Ala, Paolo De Coppi, Shahragim Tajbakhsh, Giulio Cossu, Francesco Saverio Tedesco
Satellite cells are responsible for skeletal muscle regeneration. Upon activation, they proliferate as transient amplifying myoblasts, most of which fuse into regenerating myofibers. Despite their remarkable differentiation potential, these cells have limited migration capacity, which curtails clinical use for widespread forms of muscular dystrophy. Conversely, skeletal muscle perivascular cells have less myogenic potential but better migration capacity than satellite cells. Here we show that modulation of Notch and PDGF pathways, involved in developmental specification of pericytes, induces perivascular cell features in adult mouse and human satellite cell-derived myoblasts...
February 4, 2019: Stem Cell Reports
Ying Wan, Ninghao Zhu, Yi Lu, Pak Kin Wong
The functions of RNA are tightly regulated via diverse intracellular mechanisms. However, probing the complex dynamics of endogenous RNA in live cells is a challenging task. In the present study, a DNA transformer is designed for visualizing the abundance, distribution, and mobility of endogenous mRNAs in live human cells. The transformable tetrahedral DNA (T-TED) probe has a flexible hinge structure and is programmed to conform into a 3D tetrahedron upon binding with the target mRNA. By incorporating Förster resonance energy transfer (FRET) imaging, super-resolution localization, and single particle tracking, the T-TED biosensor is applied for investigating the dynamics of Delta-like ligand 4 (Dll4) mRNA, which encodes a transmembrane protein, in human pulmonary microvascular endothelial cells...
February 5, 2019: Analytical Chemistry
Manon Jaud, Céline Philippe, Loic Van Den Berghe, Christèle Ségura, Laurent Mazzolini, Stéphane Pyronnet, Henrik Laurell, Christian Touriol
Delta-like 4 (DLL4) is a pivotal endothelium specific Notch ligand that has been shown to function as a regulating factor during physiological and pathological angiogenesis. DLL4 functions as a negative regulator of angiogenic branching and sprouting. Interestingly, Dll4 is with Vegf-a one of the few examples of haplo-insufficiency, resulting in obvious vascular abnormalities and in embryonic lethality. These striking phenotypes are a proof of concept of the crucial role played by the bioavailability of VEGF and DLL4 during vessel patterning and that there must be a very fine-tuning of DLL4 expression level...
January 25, 2019: Cancers
Rachel Boardman, Vincent Pang, Naseeb Malhi, Amy P Lynch, Lopa Leach, Andrew V Benest, David O Bates, Maria Jc Machado
The Notch ligand Delta-like ligand 4 (Dll4), upregulated by Vascular Endothelial Growth Factor (VEGF), is a key regulator of vessel morphogenesis and function, controlling tip and stalk cell selection during sprouting angiogenesis. Inhibition of Dll4 results in hyper-sprouting, non-functional, poorly perfused vessels, suggesting a role for Dll4 in formation of mature, reactive, functional vessels, with low permeability and able to restrict fluid and solute exchange. We tested the hypothesis that Dll4 controls transvascular fluid exchange...
January 25, 2019: American Journal of Physiology. Heart and Circulatory Physiology
Areerat Kunanopparat, Nattiya Hirankarn, Jiraphorn Issara-Amphorn, Pisit Tangkijvanich, Anapat Sanpavat
BACKGROUND: Notch signaling has been linked to many cancers. However, there is still limited information about the expression and role of the Notch ligand in hepatocellular carcinoma (HCC). OBJECTIVE: To investigate the expression of JAG1 and DLL4 in HCC tissues. METHODS: One hundred and forty-five HCC tissues in paraffin block since 2009 to 2016 at King Chulalongkorn Memorial hospital were assayed for JAG1 and DLL4 by immunohistochemistry...
January 13, 2019: Asian Pacific Journal of Allergy and Immunology
Yi-Fan Zhou, An-Qi Chen, Jie-Hong Wu, Ling Mao, Yuan-Peng Xia, Hui-Juan Jin, Quan-Wei He, Qing Robert Miao, Zhen-Yu Yue, Xiu-Li Liu, Ming Huang, Ya-Nan Li, Bo Hu
Angiogenesis is a crucial defense response to hypoxia that regulates the process of raising the promise of long-term neurologic recovery during the management of stroke. A high expression of antiangiogenic factors leads to the loss of neovascularization capacity in pathologic conditions. We have previously documented an impairment of the cerebral vessel perfusion and neovascularization in the cortex neighboring the stroke-induced lesion, which was accompanied by an activation of semaphorin 3E (Sema3E)/PlexinD1 after ischemic stroke...
January 17, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Wei Sun, Jing Li, Yinan Li, Jiao Zheng, Xiaoming Zhang, Xuelin Huang, Shujun Li
BACKGROUND Retinopathy of prematurity (ROP), or retrolental fibroplasia, affects premature infants who have undergone intensive care with oxygen therapy. This study aimed to investigate the inhibitory effect of the gamma-secretase inhibitor, DAPT, on neovascularization and its mechanism in a rat model of ROP. MATERIAL AND METHODS Sixty neonatal Sprague-Dawley (SD) rats included the control group (n=20), the model group (n=20), and the DAPT-treated group (n=20). The rat model of ROP was established using repeat cycles of oxygen inhalation...
January 17, 2019: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Reiner A Wimmer, Alexandra Leopoldi, Martin Aichinger, Nikolaus Wick, Brigitte Hantusch, Maria Novatchkova, Jasmin Taubenschmid, Monika Hämmerle, Christopher Esk, Joshua A Bagley, Dominik Lindenhofer, Guibin Chen, Manfred Boehm, Chukwuma A Agu, Fengtang Yang, Beiyuan Fu, Johannes Zuber, Juergen A Knoblich, Dontscho Kerjaschki, Josef M Penninger
The increasing prevalence of diabetes has resulted in a global epidemic1 . Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells2-4 . Diabetes also impairs the functions of endothelial cells5 and disturbs the communication between endothelial cells and pericytes6 . How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown...
January 16, 2019: Nature
Chaoyang Qi, Yuting Lin, Dingsheng Lin
OBJECTIVE: To determine the effect of Shu Xue Tong treatment on random skin flap survival. METHODS: Twenty-four male Sprague-Dawley (SD) rats were administered Shu Xue Tong or normal saline. On postoperative day 7, flap survival area, flap angiogenesis angiography, blood flow and vascular endothelial growth factor (VEGF), Notch1, and Delta-like ligand 4 (Dll4) expression were assessed. RESULTS: The mean flap survival area, blood vessel regeneration, microcirculatory flow, and expression of VEGF were enhanced with Shu Xue Tong treatment relative to the control...
January 15, 2019: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
Evgenii Boriushkin, Hui Zhang, Mitchell Becker, Janet Peachey, Mohammad A Shatat, Ralf H Adams, Anne Hamik
Angiogenesis is a multistep process that requires highly regulated endothelial cell (EC) behavior. The transcription factor Krüppel-like factor 4 (KLF4) is a critical regulator of several basic EC functions; we have recently shown that KLF4 disturbs pathological (tumor) angiogenesis by mediating the expression of members of VEGF and Notch signaling pathways. Notch signaling is central to orchestration of sprouting angiogenesis but little is known about the upstream regulation of Notch itself. To determine the role of KLF4 in normal (developmental) angiogenesis, we used a mouse retinal angiogenesis model...
January 3, 2019: Angiogenesis
Yichao Wang, Ruixue Yang, Xiaolin Wang, Hongfei Ci, Lei Zhou, Bo Zhu, Shiwu Wu, Danna Wang
Vasculogenic mimicry (VM) is a new blood supply style in tumors and has long been treated as a useful factor in malignant tumor metastasis and prognosis. Notch4 (a marker of Notch signaling pathway receptors), DLL4 (a marker of Notch signaling pathway ligands) and KAI1/CD82 (a suppressor gene of tumor metastasis) are all effective predictive factors for tumor metastasis. In this study, we analyzed correlations among VM, Notch4, DLL4, and KAI1/CD82 in non-small cell lung cancer (NSCLC), and their respective associations with patients' clinicopathological parameters and survival rate in NSCLC...
December 2018: Medicine (Baltimore)
Toshiaki Nakano, Shunsuke Katsuki, Mingxian Chen, Julius L Decano, Arda Halu, Lang Ho Lee, Diego V S Pestana, Angelo S T Kum, Rodrigo K Kuromoto, Whitney S Golden, Mario S Boff, Gabriel C Guimaraes, Hideyuki Higashi, Kevin J Kauffman, Takashi Maejima, Takehiro Suzuki, Hiroshi Iwata, Albert-László Barabási, Jon C Aster, Daniel G Anderson, Amitabh Sharma, Sasha A Singh, Elena Aikawa, Masanori Aikawa
BACKGROUND: Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent cardiovascular risk factor in CKD. We explored the potential impact of indoxyl sulfate on proinflammatory activation of macrophages and its underlying mechanisms. METHODS: We examined in vitro the effects of clinically relevant concentrations of indoxyl sulfate on proinflammatory responses of macrophages and the roles of organic anion transporters and organic anion transporting polypeptides (OATPs)...
January 2, 2019: Circulation
Akhilesh Kumar, Jeong Hee Lee, Kran Suknuntha, Saritha S D'Souza, Abir S Thakur, Igor I Slukvin
Human pluripotent stem cells (hPSCs) offer the potential to serve as a versatile and scalable source of T cells for immunotherapies, which could be coupled with genetic engineering technologies to meet specific clinical needs. To improve T cell production from hPSCs, it is essential to identify cell subsets that are highly enriched in T cell progenitors and those stages of development at which NOTCH activation induces the most potent T cells. In this study, we evaluated the efficacy of T cell production from cell populations isolated at different stages of hematopoietic differentiation, including mesoderm, hemogenic endothelium (HE), and multipotent hematopoietic progenitors...
December 21, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Yu Sakurai, Tomoya Hada, Akari Kato, Yuta Hagino, Wataru Mizumura, Hideyoshi Harashima
Although metastatic cancer is a major cause of death for cancer patients, no efficacious treatment for metastasis is available. We previously showed that the growth of a primary tumor could be inhibited by the administration of an anti-angiogenic small interfering RNA (siRNA) that is encapsulated in an RGD peptide-modified lipid nanoparticle (RGD-LNP). We herein report on the delivery of siRNA by an RGD-LNP to the vasculature is also effective for treating metastatic tumors. We compared the RGD-LNP with the polyethylene glycol (PEG)ylated LNP (PEG-LNP) in terms of accumulation in a lung-metastasized model...
December 21, 2018: Molecular Therapy Oncolytics
Z B Chen, M M Pu, J Yao, X Cao, L Cheng
Objective: To screen the key microRNAs targeting Notch signaling pathway in inner ear and investigate its potential regulating function. Methods: The interaction network and the Core-Notch network, involved with key genes in Notch signal pathway and differential-expressed microRNAs in inner ear, were constructed by bioinformatics methods. The important microRNAs in regulating Notch signaling pathway were screened via topological and GO analysis, followed by in vivo and in vitro investigation. Results: MiRNA-384-5p was identified as a key regulator specifically expressed in mouse brain and inner ear, which could down-regulate Notch1 ...
November 7, 2018: Zhonghua Er Bi Yan Hou Tou Jing Wai Ke za Zhi, Chinese Journal of Otorhinolaryngology Head and Neck Surgery
Guofu Zhu, Ying Lin, Hao Liu, Dongyang Jiang, Shekhar Singh, Xiankai Li, Ze Yu, Linlin Fan, Shumin Wang, Jordan Rhen, Weiming Li, Yawei Xu, Junbo Ge, Jinjiang Pang
It is well recognized that decreased vascular endothelial growth factor A (VEGF-A) mRNA plays an important role in retinal vessel regression induced by hyperoxia. However, this concept has been challenged by increasing new evidence. Furthermore, VEGF-A strongly enhances Dll4 expression and inhibition of Dll4-Notch signaling leads to excessive sprouting angiogenesis. Recently, it is shown that inactivation of Dll4-Notch1 signaling reduce hyperoxia induced vessel regression. It is unknown whether sprouting angiogenesis contributes to the protective effect or not and further investigations are needed...
December 9, 2018: Biochemical and Biophysical Research Communications
Ruihe Lin, Jingli Cai, Lawrence Kenyon, Renato Iozzo, Robert Rosenwasser, Lorraine Iacovitti
It is well documented that adult neural stem cells (NSCs) residing in the subventricular zone (SVZ) and the subgranular zone (SGZ) are induced to proliferate and differentiate into new neurons after injury such as stroke and hypoxia. However, the role of injury-related cues in driving this process and the means by which they communicate with NSCs remains largely unknown. Recently, the coupling of neurogenesis and angiogenesis and the extensive close contact between vascular cells and other niche cells, known as the neurovascular unit (NVU), has attracted interest...
November 15, 2018: Stem Cells
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