scholarly journals From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control

2021 ◽  
Vol 17 (11) ◽  
pp. e1009543
Author(s):  
Dharsan K. Soundarrajan ◽  
Francisco J. Huizar ◽  
Ramezan Paravitorghabeh ◽  
Trent Robinett ◽  
Jeremiah J. Zartman
Keyword(s):  
Experimental Studies ◽  
Tissue Level ◽  
Tissue Growth ◽  
Organ Size ◽  
Phenotypic Analysis ◽  
Final Size ◽  
Hormonal Stimulation ◽  
Signaling Dynamics ◽  
Junctional Communication ◽  
Baseline Activity

Information flow within and between cells depends significantly on calcium (Ca2+) signaling dynamics. However, the biophysical mechanisms that govern emergent patterns of Ca2+ signaling dynamics at the organ level remain elusive. Recent experimental studies in developing Drosophila wing imaginal discs demonstrate the emergence of four distinct patterns of Ca2+ activity: Ca2+ spikes, intercellular Ca2+ transients, tissue-level Ca2+ waves, and a global “fluttering” state. Here, we used a combination of computational modeling and experimental approaches to identify two different populations of cells within tissues that are connected by gap junction proteins. We term these two subpopulations “initiator cells,” defined by elevated levels of Phospholipase C (PLC) activity, and “standby cells,” which exhibit baseline activity. We found that the type and strength of hormonal stimulation and extent of gap junctional communication jointly determine the predominate class of Ca2+ signaling activity. Further, single-cell Ca2+ spikes are stimulated by insulin, while intercellular Ca2+ waves depend on Gαq activity. Our computational model successfully reproduces how the dynamics of Ca2+ transients varies during organ growth. Phenotypic analysis of perturbations to Gαq and insulin signaling support an integrated model of cytoplasmic Ca2+ as a dynamic reporter of overall tissue growth. Further, we show that perturbations to Ca2+ signaling tune the final size of organs. This work provides a platform to further study how organ size regulation emerges from the crosstalk between biochemical growth signals and heterogeneous cell signaling states.

Inverse Finite Element Modeling for Characterization of Local Elastic Properties in Image-Guided Failure Assessment of Human Trabecular Bone

2015 ◽  
Vol 137 (1) ◽  
Author(s):  
Alexander Zwahlen ◽  
David Christen ◽  
Davide Ruffoni ◽  
Philipp Schneider ◽  
Werner Schmölz ◽  
...  
Keyword(s):  
Trabecular Bone ◽  
Bone Structure ◽  
Experimental Studies ◽  
Tissue Level ◽  
Heterogeneous Distribution ◽  
Human Trabecular Bone ◽  
Young’S Moduli ◽  
Failure Assessment ◽  
Experimental Strain

The local interpretation of microfinite element (μFE) simulations plays a pivotal role for studying bone structure–function relationships such as failure processes and bone remodeling. In the past μFE simulations have been successfully validated on the apparent level, however, at the tissue level validations are sparse and less promising. Furthermore, intratrabecular heterogeneity of the material properties has been shown by experimental studies. We proposed an inverse μFE algorithm that iteratively changes the tissue level Young’s moduli such that the μFE simulation matches the experimental strain measurements. The algorithm is setup as a feedback loop where the modulus is iteratively adapted until the simulated strain matches the experimental strain. The experimental strain of human trabecular bone specimens was calculated from time-lapsed images that were gained by combining mechanical testing and synchrotron radiation microcomputed tomography (SRμCT). The inverse μFE algorithm was able to iterate the heterogeneous distribution of moduli such that the resulting μFE simulations matched artificially generated and experimentally measured strains.

scholarly journals Post-translational modifications regulate the activity of the growth restricting protease DA1

2021 ◽  
Author(s):  
Ying Chen ◽  
Dirk Inzé ◽  
Hannes Vanhaeren
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Organ Size ◽  
Negative Regulator ◽  
Renewable Energy Resources ◽  
Final Size ◽  
Post Translational Modifications ◽  
Important Trait ◽  
Multicellular Organisms ◽  
Fine Tune

Abstract Because plants are a primary food source and can form the basis for renewable energy resources, the final size of their organs is by far the most important trait to tackle when seeking increased plant productivity. Being multicellular organisms, plant organ size is mainly determined by the coordination between cell proliferation and cell expansion. The protease DA1 limits the duration of cell proliferation and hereby restricts final organ size. Since its initial identification as a negative regulator of organ growth, various transcriptional regulators of DA1, but also interacting proteins, have been identified. These interactors include cleavage substrates of DA1, but also proteins that modulate the activity of DA1 through post-translational modifications, such as ubiquitination, deubiquitination and phosphorylation. In addition, many players in the DA1 pathway display conserved phenotypes in other dicot and even monocot species. In this review, we give a timely overview of the complex, but intriguing molecular mechanisms that fine-tune the activity of DA1 and therefore final organ size, and we lay out a roadmap to identify and characterize substrates of proteases and frame the substrate cleavage events in their biological context.

scholarly journals FGF signaling dynamics regulates epithelial patterning and morphogenesis

2020 ◽  
Author(s):  
Jakub Sumbal ◽  
Tereza Vranova ◽  
Zuzana Koledova
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Mammary Epithelium ◽  
Time Lapse ◽  
Branching Morphogenesis ◽  
Tissue Level ◽  
Epithelial Tissue ◽  
Growth Factor Signaling ◽  
Fgf Signaling ◽  
Signaling Dynamics

SummarySingle cell assays revealed that growth factor signaling dynamics is actively sensed by a cell and ultimately controls cell fate. However, the effects of growth factor signaling dynamics at the tissue level have been unknown. We used mammary epithelial organoids, time-lapse imaging, fibroblast growth factor 2 (FGF2) variants of different stabilities, mathematical modeling, and perturbation analysis to study the role of FGF2 signaling dynamics in epithelial morphogenesis. We found that fluctuant and sustained FGF signaling dynamics induced distinct morphological and functional states of mammary epithelium through differential employment of intracellular effectors ERK and AKT. ERK activity domains determined epithelial branch size, while AKT activity drove epithelial stratification. Furthermore, FGF signaling dynamics affected epithelial tissue mechanoresponsiveness to extracellular matrix, thereby impinging upon branch elongation. Our study provides new insights into regulation of epithelial patterning and branching morphogenesis by FGF signaling dynamics and into downstream signaling effectors that regulate cellular outcomes.

scholarly journals Syd/JIP3 Controls Tissue Size by Regulating Diap1 Protein Turnover Downstream of Yorkie/YAP

2020 ◽  
Author(s):  
Vakil Ahmad ◽  
Gangadhar P. Vadla ◽  
Chiswili Y. Chabu
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
De Novo ◽  
Tissue Growth ◽  
Organ Size ◽  
List Type ◽  
Wing Size ◽  
Control Growth ◽  
Control Organ ◽  
Underlying Mechanisms

AbstractHow organisms control organ size is not fully understood. We found that Syd/JIP3 is required for proper wing size in Drosophila. JIP3 mutations are associated with organ size defects in mammals. The underlying mechanisms are not well understood. We discovered that Syd/JIP3 inhibition results in a downregulation of the inhibitor of apoptosis protein1 (Diap1) in the Drosophila wing. Correspondingly, Syd/JIP3 deficient tissues exhibit ectopic cell death and yield smaller wings. Syd/JIP3 inhibition generated similar effects in mammalian cells, indicating a conserved mechanism. We found that Yorkie/YAP stimulates Syd/JIP3 in Drosophila and mammalian cells. Notably, Syd/JIP3 is required for the full effect of Yorkie-mediated tissue growth. Thus Syd/JIP3 regulation of Diap1 functions downstream of Yorkie/YAP to control growth.This study provides mechanistic insights into the recent and perplexing link between JIP3 mutations and organ size defects in mammals, including in humans where de novo JIP3 variants are associated with microcephaly.HighlightsSyd/JIP3 is required for proper Drosophila wing sizeSyd/JIP3 stabilizes Diap1 to inhibit cell death in Drosophila and in mammalian cellsActivation of Yorkie/YAP stimulates Syd/JIP3Yorkie-mediated tissue growth is highly sensitive to Syd/JIP3 dosage

scholarly journals Characterization of glycoprotein IIb/IIIa-positive cells in human umbilical cord blood: their potential usefulness as megakaryocyte progenitors

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 347-355
Author(s):  
D Zucker-Franklin ◽  
JS Yang ◽  
G Grusky
Keyword(s):  
Stem Cells ◽  
Cord Blood ◽  
Experimental Studies ◽  
Cell Types ◽  
Mononuclear Leukocytes ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Phenotypic Analysis ◽  
Human Cord Blood ◽  
Hematopoietic Stem

A need for hematopoietic stem cells, particularly cells destined to enter the megakaryocyte (MK) series, prompted phenotypic analysis of mononuclear leukocytes in human cord blood. To this end, immunohistochemical, flow cytometric, and ultrastructural techniques were used. The immunogold silver enhancement method (IGS) for the detection of the MK-specific glycoprotein (GP) IIb/IIIa epitopes combined with a monocyte-specific stain for alpha-naphthyl butyrate esterase proved to be superior to flow cytometry (FACS) for precise quantitation of cell types in each sample. Immunoelectron microscopy afforded a description of distinctions between precursors bearing GPIIb/IIIa epitopes and other stem cells of the myeloid series. The number of presumed MK progenitors was surprisingly high, averaging 1.8% +/- 1.3% (range, 0.2% to 4.6%) by IGS and 4.1% +/- 3.0% (range, 0.2% to 9.3%) by FACS analysis. The occurrence of GPIIb/IIIa-positive denuded MK nuclei in cord blood was of interest, but was too small to affect these data. These observations should advocate a greater use of cord blood for restitution of MK/platelet-lineage-depleted patients as well as for experimental studies concerned with MK differentiation.

scholarly journals A Fasciclin 2 functional switch controls organ size in Drosophila

2018 ◽  
Author(s):  
Emma Velasquez ◽  
Jose A. Gomez-Sanchez ◽  
Emmanuelle Donier ◽  
Carmen Grijota-Martinez ◽  
Hugo Cabedo ◽  
...  
Keyword(s):  
Imaginal Disc ◽  
Growth Factor Receptor ◽  
Tissue Growth ◽  
Organ Size ◽  
Autonomous Function ◽  
Genetic Mosaic ◽  
Binding Partners ◽  
A Cell ◽  
Epidermal Growth ◽  
Species Specific

How cell to cell interactions control local tissue growth to attain a species-specific pattern and organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2 (Drosophila NCAM), is expressed during the development of neural and epithelial organs. Genetic mosaic analysis of Fasciclin 2 reveals two complementary and opposing functions during imaginal disc growth, a cell autonomous requirement to promote growth and an opposite non-cell autonomous function to restrain growth at high expression levels. This non-cell autonomous function is mediated by the Fasciclin 2 heterophilic-binding partners CG15630 and CG33543. We show that EGFR physically interacts with Fasciclin 2 and mediates both the cell autonomous and the non-cell autonomous function. We further show that EGFR activity in turn promotes the cell autonomous expression of Fasciclin 2. We suggest that the auto-stimulatory loop between EGFR and Fasciclin 2 operates until reaching a threshold where the Fasciclin 2 non-cell autonomous function counteracts the growth-promoting activity of the homophilic interaction to terminate imaginal disc growth. Accordingly, we have found that Fasciclin 2 limits imaginal disc growth by the end of larval development. Cellular integration of Fasciclin 2 autonomous and non-cell autonomous signaling from neighbor cells may be a key regulator component to orchestrate the rate of intercalary cell proliferation and the final size of an organ.Author SummaryOne of the key unsolved problems in Biology is how a species-specific size is attained during animal development. During development cells should compute the amount of intercalary tissue growth to stop cell proliferation when reaching a correct pattern and size. Classic studies demonstrated that local cell interactions are key in controlling organ growth to reach a correct size and pattern in vertebrates and invertebrates. We present evidence strongly suggesting that Fasciclin 2 (the ortholog of NCAM in Drosophila) functions as a growth level switch to control pattern and organ size. First, we use genetic mosaic analyses to show that Fasciclin 2 promotes organ growth in a cell autonomous manner. Then we show that Fasciclin 2 restrains growth at high expression levels in a non-cell autonomous manner, and that there is a requirement for Fasciclin 2 to limit growth by the end of larval development. This function is dependent on Fasciclin 2 heterophilic binding partners CG15630 and CG33543. The Epidermal Growth Factor receptor mediates both functional facets of Fasciclin 2 and its activity in turn increases Fasciclin 2 cell autonomous expression, suggesting the existence of a functional auto-stimulatory loop. We also show that the Epidermal Growth Factor receptor and Fasciclin 2 physically interact. Our results show that the amount of Fasciclin 2 between cells determines organ size by acting as an expression level switch for EGFR function, and suggest that other specific CAM interactions may integrate similar expression level switches acting as a code for cells to compute local growth in attaining a species-specific organ size and shape.

Development of the lateral line system in Xenopus laevis

Development ◽  
1985 ◽  
Vol 88 (1) ◽  
pp. 183-192
Author(s):  
Rudolf Winklbauer ◽  
Peter Hausen
Keyword(s):  
Cell Size ◽  
Frequency Distribution ◽  
Lateral Line ◽  
Cell Mass ◽  
Cell Number ◽  
Organ Size ◽  
Cell Counting ◽  
Lateral Line System ◽  
Final Size ◽  
Line System

During normal development of the supraorbital lateral line system of Xenopus, an elongated streak of primordial cells becomes subdivided into a linear series of cell groups containing only about eight cells each, thus forming a row of primary lateral line organs (Winklbauer & Hausen, 1983a,b). In triploid Xenopus embryos, cell size is 1·5 × normal. When the formation of lateral line organs occurs in triploid primordia, the nascent organs contain only about five or six cells each, i.e. about two thirds of normal. Thus, the increase in cell size is compensated for by a corresponding reduction in cell number, keeping constant the organ size in terms of total cell mass or volume. This result excludes a cell counting mechanism for determining organ size. In diploids, the primary organs, although being of equal size initially, differ vastly in their final size and exhibit a peculiar frequency distribution of organ sizes. A detailed quantitative model for supraorbital lateral line development has been proposed, which accounts for this characteristic frequency distribution (Winklbauer & Hausen, 1983b). This model makes precise predictions as to the frequency distribution of the final size of triploid lateral line organs, where the initial organ size is reduced to five or six cells. These predictions were verified experimentally.

Prospects for the use of thyroid hormones in patients with heart failure

2021 ◽  
Author(s):  
S. M. Pyvоvar ◽  
Yu. S. Rudyk ◽  
О. B. Krоtоva ◽  
L. V. Panina
Keyword(s):  
Heart Failure ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Animal Studies ◽  
Cardiac Tissue ◽  
Contractile Function ◽  
Heart Function ◽  
Experimental Studies ◽  
Tissue Level ◽  
Free Triiodothyronine

Thyroid hormone therapy in the setting of heart failure is still an «open book» today. There are several unanswered questions: the regimen, doses and schedule of the use of thyroid hormones, the consequences of such therapy. At the same time, the presence of a comorbid pathology of the thyroid gland, which requires the appointment of levothyroxine, allows one to partially answer these questions. Thyroid hormones affect the diastolic and systolic functions of the myocardium. Ventricular contractile function is also affected by changes in hemodynamic conditions secondary to thyroid hormones and peripheral vascular tone. Thyroid hormone homeostasis maintains a positive ventricular-arterial ratio, resulting in a favorable balance for heart function. Experimental studies in rats have shown that chronic hypothyroidism alone can eventually lead to heart failure. Other studies suggest a decrease in the level of free triiodothyronine in the myocardium after myocardial infarction or with arterial hypertension due to the activation of type 3 deiodinase, which leads to deactivation of triiodothyronine and thyroxine. To address these issues, the researchers propose conducting multicenter, randomized, placebo-controlled trials to evaluate the effects of thyroxine replacement in patients with chronic heart failure. The review highlights the growing body of evidence from animal studies and small clinical trials that suggests that low thyroid activity at the cardiac tissue level can negatively affect the progression of heart failure and that treatment with thyroid hormones can lead to an improved prognosis.

scholarly journals Comparing Individual-Based Approaches to Modelling the Self-Organization of Multicellular Tissues

2016 ◽  
Author(s):  
James M. Osborne ◽  
Alexander G. Fletcher ◽  
Joseph M. Pitt-Francis ◽  
Philip K. Maini ◽  
David J. Gavaghan
Keyword(s):  
Case Studies ◽  
Computational Models ◽  
Experimental Studies ◽  
Computational Modelling ◽  
Tissue Growth ◽  
Self Organization ◽  
Final Approval ◽  
Computational Framework ◽  
Cellular Processes ◽  
Modelling Approaches

AbstractThe coordinated behaviour of populations of cells plays a central role in tissue growth and renewal. Cells react to their microenvironment by modulating processes such as movement, growth and proliferation, and signalling. Alongside experimental studies, computational models offer a useful means by which to investigate these processes. To this end a variety of cell-based modelling approaches have been developed, ranging from lattice-based cellular automata to lattice-free models that treat cells as point-like particles or extended shapes. It is difficult to accurately compare between different modelling approaches, since one cannot distinguish between differences in behaviour due to the underlying model assumptions and those due to differences in the numerical implementation of the model. Here, we exploit the availability of an implementation of five popular cell-based modelling approaches within a consistent computational framework, Chaste (http://www.cs.ox.ac.uk/chaste). This framework allows one to easily change constitutive assumptions within these models. In each case we provide full details of all technical aspects of our model implementations. We compare model implementations using four case studies, chosen to reflect the key cellular processes of proliferation, adhesion, and short-and long-range signalling. These case studies demonstrate the applicability of each model and provide a guide for model usage.Authors’ contributionsJO and AF conceived of the study, designed the study, coordinated the study, carried out the computational modelling and drafted the manuscript. JP contributed to the computational modelling and helped draft the manuscript. PM and DG conceived of the study, designed the study and helped draft the manuscript. All authors gave final approval for publication.

scholarly journals Fibroblast growth factor is predicted to dominate MAPK activation by pro-angiogenic factors

2018 ◽  
Author(s):  
Min Song ◽  
Stacey D. Finley
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Intracellular Signaling ◽  
Dominant Role ◽  
Experimental Studies ◽  
Mapk Signaling ◽  
Tissue Growth ◽  
Angiogenic Factors ◽  
Mitogen Activated Protein Kinase ◽  
Fibroblast Growth

AbstractAngiogenesis is important in physiological and pathological conditions, as blood vessels provide nutrients and oxygen needed for tissue growth and survival. Therefore, targeting angiogenesis is a prominent strategy in both tissue engineering and cancer treatment. However, not all of the approaches to promote or inhibit angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation, and there is a limited understanding of how these promoters combine together to stimulate angiogenesis. Thus, more quantitative insight is needed to understand their interactions. In this study, we have trained and validated a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling and phosphorylation of extracellular regulated kinase (ERK), which promote cell proliferation. We apply the model to predict the dynamics of phosphorylated ERK (pERK) in response to the stimulation by FGF and VEGF individually and in combination. The model predicts that FGF plays a dominant role in promoting ERK phosphorylation, compared to VEGF. The modeling predictions show that VEGFR2 density and trafficking parameters significantly influence the level of VEGF-induced pERK. The model matches experimental data and is a framework to synthesize and quantitatively explain experimental studies. Ultimately, the model provides mechanistic insight into FGF and VEGF interactions needed to identify potential targets for pro-or anti-angiogenic therapies.

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