scholarly journals Single-Cell Integration Analysis of Heterotopic Ossification and Fibrocartilage Developmental Lineage: Endoplasmic Reticulum Stress Effector Xbp1 Transcriptionally Regulates the Notch Signaling Pathway to Mediate Fibrocartilage Differentiation

2021 ◽  
Vol 2021 ◽  
pp. 1-29
Author(s):  
Yisheng Chen ◽  
Yaying Sun ◽  
Yuzhen Xu ◽  
Wei-Wei Lin ◽  
Zhiwen Luo ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Single Cell ◽  
Heterotopic Ossification ◽  
Signaling Pathway ◽  
Transcriptional Regulators ◽  
Notch Signaling Pathway ◽  
Ectopic Ossification ◽  
Systematic Analysis ◽  
Accessible Chromatin ◽  
Integration Analysis

Introduction. Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes. Methods. This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified. Results. HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke. Conclusion. A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand–receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.

Regulation of EMT by Notch Signaling Pathway in Tumor Progression

2013 ◽  
Vol 13 (9) ◽  
pp. 957-962 ◽  
Author(s):  
Yumei Li ◽  
Jia Ma ◽  
Xiujuan Qian ◽  
Qiong Wu ◽  
Jun Xia ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway

Andrographolide Inhibits Proliferation of Colon Cancer SW-480 Cells via Downregulating Notch Signaling Pathway.

2020 ◽  
Vol 20 ◽  
Author(s):  
Imran Khan ◽  
Sadaf Mahfooz ◽  
Mohd Saeed ◽  
Irfan Ahmad ◽  
Irfan A. Ansari
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Mtt Assay ◽  
Annexin V ◽  
Notch Signaling Pathway ◽  
Phase Cell ◽  
Ros Generation ◽  
Notch 1

Background: Recently Notch signaling pathway has gained attention as a potential therapeutic target for chemotherapeutic intervention. However, the efficacy of previously known Notch inhibitors in colon cancer is still unclear. The purpose of this study was to investigate the effect of andrographolide on aberrantly activated Notch signaling in SW-480 cells in vitro. Methods: The cytostatic potential of andrographolide on SW-480 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay, morphology assessment and colony formation assay. The apoptotic activity was evaluated by FITC Annexin V assay, 4′,6-diamidino-2-phenylindole (DAPI), Hoechst, Rhodamine 123 and Mito Tracker CMXRos staining. Scratch assay for migratory potential assessment. 7’-Dichlorodihydrofluorescein Diacetate (DCFH-DA) staining was used to evaluate the Reactive Oxygen Species (ROS) generation. Relative mRNA expression of Bax, Bcl2, NOTCH 1 and JAGGED 1 was estimated by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). Cell cycle phase distribution was evaluated Annexin V-FITC/PI staining. Results: MTT assay demonstrated dose and time dependent cytoxicity of andrographolide on SW-480 cells. It also inhibited the migratory and colony forming potential of SW-480 cells. Furthermore, andrographolide also showed disruption of mitochondrial membrane potential and induced apoptosis through nuclear condensation. Flow cytometric evaluation showed andrographolide enhanced early and late apoptotic cells and induced upregulation of proapoptotic (Bax and Bad) and downregulation of antiapoptotic Bcl2 in treated SW-480 cells. Andrographolide augmented intracellular ROS generation and induced G0/G1 phase cell cycle arrest in colon cancer SW480 cells. Furthermore, andrographolide repressed the Notch signaling by decreasing the expression of NOTCH 1 and JAGGED 1. Conclusion: Our findings suggested that andrographolide constraint the growth of SW-480 cells through the inhibition of Notch signaling pathway.

Notch signaling pathway in infectious diseases: role in the regulation of immune response

2021 ◽  
Vol 70 (3) ◽  
pp. 261-274
Author(s):  
Ricardo Cardoso Castro ◽  
Relber Aguiar Gonçales ◽  
Fabiana Albani Zambuzi ◽  
Fabiani Gai Frantz
Keyword(s):  
Immune Response ◽  
Infectious Diseases ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway

scholarly journals Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1264-1273 ◽  
Author(s):  
Melanie G. Cornejo ◽  
Vinciane Mabialah ◽  
Stephen M. Sykes ◽  
Tulasi Khandan ◽  
Cristina Lo Celso ◽  
...  
Keyword(s):  
Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Differentiation ◽  
Notch Signaling Pathway ◽  
Developmental Pathways ◽  
Lineage Specification ◽  
Hematopoietic Stem

Abstract The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways.

scholarly journals Mathematical analysis of the effect of portal vein cells on biliary epithelial cell differentiation through the Delta-Notch signaling pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Masaharu Yoshihara ◽  
Teppei Nishino ◽  
Manoj Kumar Yadav ◽  
Akihiro Kuno ◽  
Takeshi Nagata ◽  
...  
Keyword(s):  
Portal Vein ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Target Genes ◽  
Notch Signaling Pathway ◽  
Epithelial Differentiation ◽  
Production Rates ◽  
Fine Grained ◽  
Downstream Target ◽  
Notch Receptors

Abstract Objective The Delta-Notch signaling pathway induces fine-grained patterns of differentiation from initially homogeneous progenitor cells in many biological contexts, including Drosophila bristle formation, where mathematical modeling reportedly suggests the importance of production rate of the components of this signaling pathway. In contrast, the epithelial differentiation of bile ducts in the developing liver is unique in that it occurs around the portal vein cells, which express extremely high amounts of Delta ligands and act as a disturbance for the amount of Delta ligands in the field by affecting the expression levels of downstream target genes in the cells nearby. In the present study, we mathematically examined the dynamics of the Delta-Notch signaling pathway components in disturbance-driven biliary differentiation, using the model for fine-grained patterns of differentiation. Results A portal vein cell induced a high Notch signal in its neighboring cells, which corresponded to epithelial differentiation, depending on the production rates of Delta ligands and Notch receptors. In addition, this epithelial differentiation tended to occur in conditions where fine-grained patterning was reported to be lacking. These results highlighted the potential importance of the stability towards homogeneity determined by the production rates in Delta ligands and Notch receptors, in a disturbance-dependent epithelial differentiation.

The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1989-1997 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Ganesh Kolumam ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Lymphatic Vessels ◽  
Mouse Skin ◽  
Notch Signaling Pathway ◽  
Cell Phenotype ◽  
Mural Cell ◽  
Lymphatic Development ◽  
Vessel Development

Abstract The Notch signaling pathway plays a fundamental role during blood vessel development. Notch signaling regulates blood vessel morphogenesis by promoting arterial endothelial differentiation and pro-viding spatial and temporal control over “tip cell” phenotype during angiogenic sprouting. Components of the Notch signaling pathway have emerged as potential regulators of lymphatic development, joining the increasing examples of blood vessel regulators that are also involved in lymphatic development. However, in mammals a role for the Notch signaling pathway during lymphatic development remains to be demonstrated. In this report, we show that blockade of Notch1 and Dll4, with specific function-blocking antibodies, results in defective postnatal lymphatic development in mice. Mechanistically, Notch1-Dll4 blockade is associated with down-regulation of EphrinB2 expression, been shown to be critically involved in VEGFR3/VEGFC signaling, resulting in reduced lymphangiogenic sprouting. In addition, Notch1-Dll4 blockade leads to compromised expression of distinct lymphatic markers and to dilation of collecting lymphatic vessels with reduced and disorganized mural cell coverage. Finally, Dll4-blockade impairs wound closure and severely affects lymphangiogenesis during the wound healing in adult mouse skin. Thus, our study demonstrates for the first time in a mammalian system that Notch1-Dll4 signaling pathway regulates postnatal lymphatic development and pathologic lymphangiogenesis.

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