scholarly journals Biallelic PI4KA variants cause neurological, intestinal and immunological disease

Brain ◽  
2021 ◽  
Author(s):  
Claire G Salter ◽  
Yiying Cai ◽  
Bernice Lo ◽  
Guy Helman ◽  
Henry Taylor ◽  
...  
Keyword(s):  
Cell Types ◽  
Intestinal Atresia ◽  
Lipid Kinase ◽  
Organ Specific ◽  
Modelling Studies ◽  
Multiple Cell ◽  
Inflammatory Bowel ◽  
Phosphatidylinositol 4 ◽  
Multiple Intestinal Atresia ◽  
Insight Into

Abstract Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes likely stem from impairment of molecular roles requiring organ specific PI4KIIIα-TTC7-FAM126 complex functional interactions. Together these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.

Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Disease and Perspectives for Therapeutic Implication

2017 ◽  
Vol 35 (1-2) ◽  
pp. 25-31 ◽  
Author(s):  
Dominik Bettenworth ◽  
Florian Rieder
Keyword(s):  
Inflammatory Bowel Disease ◽  
Chronic Inflammation ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Stricture Formation ◽  
Intestinal Fibrosis ◽  
Conventional View ◽  
Multiple Cell ◽  
Inflammatory Bowel

Background: Intestinal fibrosis with stricture formation is a common feature of inflammatory bowel disease (IBD) and leads to a significantly impaired quality of life in affected patients, intestinal obstruction as well as to the need for surgical intervention. This constitutes a major treatment challenge. Key Messages: Fibrosis results from the response of gut tissue to the insult inflicted by chronic inflammation. Similarly to what occurs in other organs, the underlying fibrogenic mechanisms are complex and dynamic, involving multiple cell types, interrelated cellular events, and a large number of soluble factors. Owing to a breakdown of the epithelial barrier in IBD, luminal bacterial products leak into the interstitium and induce an innate immune response mediated by the activation of both immune and non-immune cells. Other environmental factors as well as chronic inflammation will certainly impact the quality and quantity of intestinal fibrosis. Finally, the composition of the intestinal extracellular matrix is dramatically altered in chronic gut inflammation and actively promotes fibrosis through its mechanical properties. The conventional view that intestinal fibrosis is an inevitable and irreversible process is gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline its pathogenesis. In addition, clinical observations in patients who undergo strictureplasty have shown that stricture formation is reversible. Conclusions: Identification of the unique mechanisms of intestinal fibrogenesis should create a practical framework to target and block specific fibrogenic pathways, estimate the risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, allow the development of treatment methods customized to each patient's type and degree of intestinal fibrosis.

scholarly journals A Single Cell Transcriptomic Atlas Characterizes Aging Tissues in the Mouse

2019 ◽  
Author(s):  
◽  
Angela Oliveira Pisco ◽  
Aaron McGeever ◽  
Nicholas Schaum ◽  
Jim Karkanias ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Types ◽  
Cell Type ◽  
Cellular Processes ◽  
Progressive Loss ◽  
Age Related ◽  
Multiple Cell ◽  
Cell Type Specific ◽  
Molecular Information ◽  
Insight Into

AbstractAging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes which underlie progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes we have created a single cell transcriptomic atlas across the life span of Mus musculus which includes data from 23 tissues and organs. We discovered cell-specific changes occurring across multiple cell types and organs, as well as age related changes in the cellular composition of different organs. Using single-cell transcriptomic data we were able to assess cell type specific manifestations of different hallmarks of aging, such as senescence3, genomic instability4 and changes in the organism’s immune system2. This Tabula Muris Senis provides a wealth of new molecular information about how the most significant hallmarks of aging are reflected in a broad range of tissues and cell types.

scholarly journals Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease

PLoS Genetics ◽  
2016 ◽  
Vol 12 (3) ◽  
pp. e1005908 ◽  
Author(s):  
James E. Peters ◽  
Paul A. Lyons ◽  
James C. Lee ◽  
Arianne C. Richard ◽  
Mary D. Fortune ◽  
...  
Keyword(s):  
Cell Types ◽  
Eqtl Mapping ◽  
Immune Mediated ◽  
Multiple Cell ◽  
Insight Into

scholarly journals Spatiotemporal Regulation of Cell–Cell Adhesions

2021 ◽  
Author(s):  
Brent M. Bijonowski
Keyword(s):  
Cell Adhesion ◽  
Red Light ◽  
Cell Types ◽  
Spatiotemporal Regulation ◽  
Different Types ◽  
Multiple Cell ◽  
Cell Adhesions ◽  
Different Cell Types ◽  
Insight Into ◽  
Cell Cell

Cell–cell adhesions are fundamental in regulating multicellular behavior and lie at the center of many biological processes from embryoid development to cancer development. Therefore, controlling cell–cell adhesions is fundamental to gaining insight into these phenomena and gaining tools that would help in the bioartificial construction of tissues. For addressing biological questions as well as bottom-up tissue engineering the challenge is to have multiple cell types self-assemble in parallel and organize in a desired pattern from a mixture of different cell types. Ideally, different cell types should be triggered to self-assemble with different stimuli without interfering with the other and different types of cells should sort out in a multicellular mixture into separate clusters. In this chapter, we will summarize the developments in photoregulation cell–cell adhesions using non-neuronal optogenetics. Among the concepts, we will cover is the control of homophylic and heterophilic cell–cell adhesions, the independent control of two different types with blue or red light and the self-sorting of cells into distinct structures and the importance of cell–cell adhesion dynamics. These tools will give an overview of how the spatiotemporal regulation of cell–cell adhesion gives insight into their role and how tissues can be assembled from cells as the basic building block.

ADVANCED TISSUE ENGINEERING STRATEGIES FOR VASCULARIZED PARENCHYMAL CONSTRUCTS

2014 ◽  
Vol 14 (01) ◽  
pp. 1430001 ◽  
Author(s):  
JIANKANG HE ◽  
FENG XU ◽  
YAXIONG LIU ◽  
ZHONGMIN JIN ◽  
DICHEN LI
Keyword(s):  
Tissue Engineering ◽  
Cell Types ◽  
Great Promise ◽  
Top Down ◽  
Bottom Up ◽  
Organ Specific ◽  
Recent Developments ◽  
Multiple Cell ◽  
Complex Structural

The fabrication of vascularized parenchymal organs to alleviate donor shortage in organ transplantation is the holy grail of tissue engineering. However, conventional tissue-engineering strategies have encountered huge challenges in recapitulating complex structural organization of native organs (e.g., orderly arrangement of multiple cell types and vascular network), which plays an important role in engineering functional vascularized parenchymal constructs in vitro. Recent developments of various advanced tissue-engineering strategies have exhibited great promise in replicating organ-specific architectures into artificial constructs. Here, we review the recent advances in top-down and bottom-up strategies for the fabrication of vascularized parenchymal constructs. We highlight the fabrication of microfluidic scaffolds potential for nutrient transport or vascularization as well as the controlled multicellular arrangement. The advantages as well as the limitations associated with these strategies will be discussed. It is envisioned that the combination of microfluidic concept in top-down strategies and multicellular arrangement concept in bottom-up strategies could potentially generate new insights for the fabrication of vascularized parenchymal organs.

scholarly journals Mesothelial mobilization in the developing lung and heart differs in timing, quantity, and pathway dependency

2019 ◽  
Vol 316 (5) ◽  
pp. L767-L783 ◽  
Author(s):  
Timo H. Lüdtke ◽  
Carsten Rudat ◽  
Jennifer Kurz ◽  
Regine Häfner ◽  
Franziska Greulich ◽  
...  
Keyword(s):  
Mesenchymal Cell ◽  
Cell Types ◽  
Organ Specificity ◽  
Visceral Pleura ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Developing Heart ◽  
Organ Specific ◽  
Canonical Wnt ◽  
Insight Into

The mesothelial lining of the lung, the visceral pleura, and of the heart, the epicardium, derive from a common multipotent precursor tissue, the mesothelium of the embryonic thoracic cavity that also contributes to organ-specific mesenchymal cell types. Insight into mesothelial mobilization and differentiation has prevailedin the developing heart while the mesenchymal transition and fate of the visceral pleura are poorly understood. Here, we use the fact that the early mesothelium of both the lung and the heart expresses the transcription factor gene Wt1, to comparatively analyze mesothelial mobilization in the two organs by a genetic cre-loxP-based conditional approach. We show that epicardial cells are mobilized in a large number between E12.5 and E14.5, whereas pleural mobilization occurs only sporadically and variably in few regions of the lung in a temporally highly confined manner shortly after E12.5. Mesothelium-specific inactivation of unique pathway components using a Wt1creERT2line excluded a requirement for canonical WNT, NOTCH, HH, TGFB, PDGFRA, and FGFR1/FGFR2 signaling in the mesenchymal transition of the visceral pleura but indicated a deleterious effect of activated WNT, NOTCH, and HH signaling on lung development. Epicardial mobilization was negatively impacted on by loss of HH, PDGFRA, FGFR1/2 signaling. Epicardial overactivation of WNT, NOTCH, and HH disturbed epicardial and myocardial integrity. We conclude that mesothelial mobilization in the developing lung and heart differs in timing, quantity and pathway dependency, indicating the organ specificity of the program.

scholarly journals Angiogenesis in Inflammatory Bowel Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Canan Alkim ◽  
Huseyin Alkim ◽  
Ali Riza Koksal ◽  
Salih Boga ◽  
Ilker Sen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Cell Types ◽  
Research Area ◽  
Complex Process ◽  
Multiple Cell ◽  
Inflammatory Bowel ◽  
New Research ◽  
Chronic Intestinal Inflammation

Angiogenesis is an important component of pathogenesis of inflammatory bowel disease (IBD). Chronic inflammation and angiogenesis are two closely related processes. Chronic intestinal inflammation is dependent on angiogenesis and this angiogenesis is modulated by immune system in IBD. Angiogenesis is a very complex process which includes multiple cell types, growth factors, cytokines, adhesion molecules, and signal transduction. Lymphangiogenesis is a new research area in the pathogenesis of IBD. While angiogenesis supports inflammation via leukocyte migration, carrying oxygen and nutrients, on the other hand, it has a major role in wound healing. Angiogenic molecules look like perfect targets for the treatment of IBD, but they have risk for serious side effects because of their nature.

scholarly journals Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms

2021 ◽  
Vol 3 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Alexandra A. C. Newman ◽  
Vlad Serbulea ◽  
Richard A. Baylis ◽  
Laura S. Shankman ◽  
Xenia Bradley ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Cell Types ◽  
Fibrous Cap ◽  
Multiple Cell
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