scholarly journals ­PlGF Regulates Angiopoietin-1 and Tie-2 Expression in Human Retinal Endothelial Cell-Pericyte Cocultures and iPSC-Derived Vascular Organoids through VEGFR1

2021 ◽  
Author(s):  
Hu Huang ◽  
Madhu Saddala ◽  
Rajiv Ravindra Mohan
Keyword(s):  
Cell Function ◽  
Cell Types ◽  
Experimental Models ◽  
Receptor Expression ◽  
Therapeutic Interventions ◽  
Dependent Manner ◽  
Sequencing Data ◽  
Vascular Cell ◽  
Diabetic Vasculopathy ◽  
Induced Pluripotent

Abstract Placental growth factor (PlGF) and Angiopoietin (Ang)-1 are two angiogenic factors that play vital roles in vascular cell growth and stabilization. The present study's objective is to examine PlGF's regulation of Ang-1 and its Tie-2 receptor expression in human vascular cells and vasculature. We exploited the cocultures of human primary retinal endothelial cells (HREC) and pericytes (HRP) and the blood vessel or vascular organoids derived from human-induced pluripotent stem cells (iPSC) as experimental models. In the HREC-HRP cocultures, PlGF blockage upregulated the expressions of Ang-1 and Tie-2 in an antibody dose-dependent manner. Upregulation of Ang-1 and Tie-2 by PlGF blockade did not occur in HREC and HRP monocultures but only in HREC-HRP cocultures, indicating the interactions of the two cell types. VEGFR1 inhibition diminished Ang-1 and Tie-2 upregulation caused by PlGF blockade and reduced pericyte variability in high glucose conditions. In the iPSC-derived vascular organoids (VO), PlGF, Ang-1, and Ang-2 were expressed mainly by perivascular cells. Bioinformatics analysis of RNA sequencing data revealed that diabetes-mimicking conditions upregulated PlGF and Ang-2 expressions in the VO cultures. PlGF blockade upregulated Ang-1 and Tie-2 expression and promoted pericyte coverage and association with ECs in the VO. Together, the data suggest that PlGF regulates Ang-1 and Tie-2 expression in part through VEGFR1, which is involved in vascular cell function and stabilization. The findings may help design new therapeutic interventions for diabetic vasculopathy, such as diabetic macular edema and proliferative diabetic retinopathy, by targeting PlGF and Ang signaling pathways.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

scholarly journals Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types

2017 ◽  
Author(s):  
Jingqi QX Gong ◽  
Eric A Sobie
Keyword(s):  
Pluripotent Stem Cells ◽  
Cardiac Electrophysiology ◽  
Cell Types ◽  
Population Based ◽  
Experimental Models ◽  
Mechanistic Modeling ◽  
Type Model ◽  
Cell Type ◽  
Drug Responses ◽  
Induced Pluripotent

ABSTRACTQuantitative mismatches between human physiology and experimental models can present serious limitations for the development of effective therapeutics. We addressed this issue, in the context of cardiac electrophysiology, through mechanistic mathematical modeling combined with statistical analyses. Physiological metrics were simulated in heterogeneous populations describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs). These simulated measures were used to construct a cross-cell type regression model that predicts adult myocyte drug responses from iPSC-CM behaviors. We found that quantitatively accurate predictions of responses to selective or non-selective drugs could be generated based on iPSC-CM responses and that the method can be extended to predict drug responses in diseased as well as healthy cells. This cross-cell type model can be of great value in drug development, and the approach, which can be applied to other fields, represents an important strategy for overcoming experimental model limitations.

scholarly journals An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

2020 ◽  
Author(s):  
Jerome Robert ◽  
Nicholas Weilinger ◽  
Li-Ping Zao ◽  
Stefano Cataldi ◽  
Emily Button ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurovascular Unit ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Experimental Models ◽  
Flow Conditions ◽  
Anatomy And Physiology ◽  
Induced Pluripotent

Abstract Introduction: The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently noin vitro3-dimensional (3D) perfusible model of the human cortical arterial NVU. Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It also reproduces key characteristics of cortical neurons and astrocytes, as well as the formation of a selective and functional endothelial barrier. We further provide proof-of-principle that our in vitro human arterial NVU may be suitable to study neurodegenerative diseases such as Alzheimer’s disease (AD), as we report both phosphorylated tau and beta-amyloid accumulation in our model over time. Finally, we show that our arterial NVU model enables the study of neuronal and glial fluid biomarkers. Conclusion: This model is a suitable tool to investigate arterial NVU functions such as neuronal electrophysiology in health and disease. Further the design of platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

scholarly journals An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

2020 ◽  
Author(s):  
Jerome Robert ◽  
Nicholas Weilinger ◽  
Li-Ping Zao ◽  
Stefano Cataldi ◽  
Emily Button ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurovascular Unit ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Experimental Models ◽  
Flow Conditions ◽  
Anatomy And Physiology ◽  
Induced Pluripotent

Abstract Introduction: The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.Conclusion: This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

scholarly journals Proteomics in the World of Induced Pluripotent Stem Cells

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 703 ◽  
Author(s):  
Rafael Soares Lindoso ◽  
Tais H. Kasai-Brunswick ◽  
Gustavo Monnerat Cahli ◽  
Federica Collino ◽  
Adriana Bastos Carvalho ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cell Function ◽  
State Of The Art ◽  
Embryonic Stem ◽  
Cell Types ◽  
Molecular Signaling ◽  
Induced Pluripotent

Omics approaches have significantly impacted knowledge about molecular signaling pathways driving cell function. Induced pluripotent stem cells (iPSC) have revolutionized the field of biological sciences and proteomics and, in particular, has been instrumental in identifying key elements operating during the maintenance of the pluripotent state and the differentiation process to the diverse cell types that form organisms. This review covers the evolution of conceptual and methodological strategies in proteomics; briefly describes the generation of iPSC from a historical perspective, the state-of-the-art of iPSC-based proteomics; and compares data on the proteome and transcriptome of iPSC to that of embryonic stem cells (ESC). Finally, proteomics of healthy and diseased cells and organoids differentiated from iPSC are analyzed.

scholarly journals Generation of a Panel of Induced Pluripotent Stem Cells From Chimpanzees: a Resource for Comparative Functional Genomics

2014 ◽  
Author(s):  
Irene Gallego Romero ◽  
Bryan J Pavlovic ◽  
Irene Hernando-Herraez ◽  
Nicholas E Banovich ◽  
Courtney L Kagan ◽  
...  
Keyword(s):  
Somatic Cells ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Model Systems ◽  
Sequencing Data ◽  
Differentiation Potential ◽  
Culture Techniques ◽  
Human Ipscs ◽  
Wide Range ◽  
Induced Pluripotent

Comparative genomics studies in primates are extremely restricted because we only have access to a few types of cell lines from non-human apes and to a limited collection of frozen tissues. In order to gain better insight into regulatory processes that underlie variation in complex phenotypes, we must have access to faithful model systems for a wide range of tissues and cell types. To facilitate this, we have generated a panel of 7 fully characterized chimpanzee (Pan troglodytes) induced pluripotent stem cell (iPSC) lines derived from fibroblasts of healthy donors. All lines appear to be free of integration from exogenous reprogramming vectors, can be maintained using standard iPSC culture techniques, and have proliferative and differentiation potential similar to human and mouse lines. To begin demonstrating the utility of comparative iPSC panels, we collected RNA sequencing data and methylation profiles from the chimpanzee iPSCs and their corresponding fibroblast precursors, as well as from 7 human iPSCs and their precursors, which were of multiple cell type and population origins. Overall, we observed much less regulatory variation within species in the iPSCs than in the somatic precursors, indicating that the reprogramming process has erased many of the differences observed between somatic cells of different origins. We identified 4,918 differentially expressed genes and 3,598 differentially methylated regions between iPSCs of the two species, many of which are novel inter-species differences that were not observed between the somatic cells of the two species. Our panel will help realise the potential of iPSCs in primate studies, and in combination with genomic technologies, transform studies of comparative evolution.

scholarly journals Vascular CaMKII: heart and brain in your arteries

2016 ◽  
Vol 311 (3) ◽  
pp. C462-C478 ◽  
Author(s):  
Fanny Toussaint ◽  
Chimène Charbel ◽  
Bruce G. Allen ◽  
Jonathan Ledoux
Keyword(s):  
Cellular Proliferation ◽  
Cell Function ◽  
Vascular System ◽  
Splice Variants ◽  
Cell Types ◽  
Cellular Functions ◽  
Vascular Cell ◽  
Calcium Calmodulin Dependent ◽  
Regulatory Processes ◽  
Neuronal Tissues

First characterized in neuronal tissues, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key signaling component in several mammalian biological systems. Its unique capacity to integrate various Ca2+ signals into different specific outcomes is a precious asset to excitable and nonexcitable cells. Numerous studies have reported roles and mechanisms involving CaMKII in brain and heart tissues. However, corresponding functions in vascular cell types (endothelium and vascular smooth muscle cells) remained largely unexplored until recently. Investigation of the intracellular Ca2+ dynamics, their impact on vascular cell function, the regulatory processes involved and more recently the spatially restricted oscillatory Ca2+ signals and microdomains triggered significant interest towards proteins like CaMKII. Heteromultimerization of CaMKII isoforms (four isoforms and several splice variants) expands this kinase's peculiar capacity to decipher Ca2+ signals and initiate specific signaling processes, and thus controlling cellular functions. The physiological functions that rely on CaMKII are unsurprisingly diverse, ranging from regulating contractile state and cellular proliferation to Ca2+ homeostasis and cellular permeability. This review will focus on emerging evidence of CaMKII as an essential component of the vascular system, with a focus on the kinase isoform/splice variants and cellular system studied.

scholarly journals An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jerome Robert ◽  
Nicholas L. Weilinger ◽  
Li-Ping Cao ◽  
Stefano Cataldi ◽  
Emily B. Button ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurovascular Unit ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Experimental Models ◽  
Flow Conditions ◽  
Anatomy And Physiology ◽  
Induced Pluripotent

Abstract Introduction The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU. Method We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. Results This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model. Conclusion This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

scholarly journals NK3R Mediates the EGF-Induced SLα Secretion and mRNA Expression in Grass Carp Pituitary

2018 ◽  
Vol 20 (1) ◽  
pp. 91 ◽  
Author(s):  
Xiangfeng Qin ◽  
Cheng Ye ◽  
Xiaoyun Zhou ◽  
Jingyi Jia ◽  
Shaohua Xu ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Grass Carp ◽  
Cell Function ◽  
Cell Types ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Lower Vertebrates ◽  
Mrna And Protein Expression

Epidermal growth factor (EGF) is a potent regulator of cell function in many cell types. In mammals, the EGF/EGFR system played an important role in both pituitary physiology and pathology. However, it is not clear about the pituitary action of EGF in lower vertebrates. In this study, using grass carp as a model, we found that EGF could stimulate NK3R mRNA and protein expression through pituitary ErbB1 and ErbB2 coupled to MEK/ERK and PI3K/Akt/mTOR pathways. In addition, EGF could also induce pituitary somatolactin α (SLα) secretion and mRNA expression in a dose- and time-dependent manner in vivo and in vitro. The stimulatory actions of EGF on SLα mRNA expression were also mediated by PI3K/Akt/mTOR and MEK/ERK pathways coupled to ErbB1 and ErbB2 activation. Our previous study has reported that neurokinin B (NKB) could also induce SLα secretion and mRNA expression in carp pituitary cells. In the present study, interestingly, we found that EGF could significantly enhance NKB-induced SLα mRNA expression. Further studies found that NK3R antagonist SB222200 could block EGF-induced SLα mRNA expression, indicating an NK3R requirement. Furthermore, cAMP/PKA inhibitors and PLC/PKC inhibitors could both abolish EGF- and EGF+NKB-induced SLα mRNA expression, which further supported that EGF-induced SLα mRNA expression is NK3R dependent.

scholarly journals Uncovering hypergraphs of cell-cell interaction from single cell RNA-sequencing data

2019 ◽  
Author(s):  
Koki Tsuyuzaki ◽  
Manabu Ishii ◽  
Itoshi Nikaido
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Cell Types ◽  
Cell Interaction ◽  
Receptor Expression ◽  
Sequencing Data ◽  
Sequencing Technologies ◽  
Single Cell Rna Sequencing ◽  
Ligand Expression ◽  
Cell Cell

AbstractComplex biological systems can be described as a multitude of cell-cell interactions (CCIs). Recent single-cell RNA-sequencing technologies have enabled the detection of CCIs and related ligand-receptor (L-R) gene expression simultaneously. However, previous data analysis methods have focused on only one-to-one CCIs between two cell types. To also detect many-to-many CCIs, we proposescTensor, a novel method for extracting representative triadic relationships (hypergraphs), which include (i) ligand-expression, (ii) receptor-expression, and (iii) L-R pairs. When applied to simulated and empirical datasets,scTensorwas able to detect some hypergraphs including paracrine/autocrine CCI patterns, which cannot be detected by previous methods.

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