Stochastic intracellular regulation can remove oscillations in a model of tissue growth

2020 ◽  
Vol 37 (4) ◽  
pp. 551-568
Author(s):  
M Banerjee ◽  
V Volpert
Keyword(s):  
Cell Fate ◽  
Random Variable ◽  
Cell Number ◽  
Tissue Growth ◽  
Initial Condition ◽  
Differentiated Cells ◽  
Intracellular Regulation ◽  
Bistable Dynamics ◽  
Intracellular Proteins

Abstract The work is devoted to the analysis of cell population dynamics where cells make a choice between differentiation and apoptosis. This choice is based on the values of intracellular proteins whose concentrations are described by a system of ordinary differential equations with bistable dynamics. Intracellular regulation and cell fate are controlled by the extracellular regulation through the number of differentiated cells. It is shown that the total cell number necessarily oscillates if the initial condition in the intracellular regulation is fixed. These oscillations can be suppressed if the initial condition is a random variable with a sufficiently large variation. Thus, the result of the work suggests a possible answer to the question about the role of stochasticity in the intracellular regulation.

scholarly journals Intestinal progenitor P-bodies maintain stem cell identity by suppressing pro-differentiation factors

2020 ◽  
Author(s):  
Kasun Buddika ◽  
Yi-Ting Huang ◽  
Alex Butrum-Griffith ◽  
Sam A. Norrell ◽  
Alex M. O’Connor ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Transcriptional Control ◽  
Adult Stem Cell ◽  
Loss Of Function ◽  
P Bodies ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Stem Cell Populations

AbstractPost-transcriptional gene regulatory mechanisms allow cells to quickly respond to environmental variation without relying on nascent transcription. However, the role of these mechanisms in cell fate transitions in adult stem cell populations remain poorly understood. We address this question here by investigating the role of Processing bodies (P-bodies), a key site of post-transcriptional control, in adult Drosophila intestinal stem cells. We report that this cell type, but not surrounding differentiated cells, harbor P-bodies that contain Drosophila orthologs of mammalian P-body components DDX6, EDC3, EDC4 and LSM14A/B and are ultrastructurally organized in a “core-shell” structure. A targeted RNAi screen identified 100+ genes that affect normal P-body morphology including patr-1, which is required for mature P-body assembly. Using both verified patr-1 RNAi strains and newly generated patr-1 loss-of-function alleles, we show that P-body assembly defects correlate with loss of intestinal progenitors. RNA-seq analysis found that patr-1 mutant progenitors inappropriately express enterocyte (EC)-specific genes, leading to precocious EC differentiation. We further demonstrate that this process is independent of well-known transcriptional repressor escargot, indicating P-body-dependent post-transcriptional regulation of pro-differentiation genes. Taken together, this work delineates the importance of post-transcriptional mechanisms in adult stem cell maintenance.

scholarly journals Yap/Taz-TEAD ACTIVITY LINKS MECHANICAL CUES TO CELL PROGENITOR BEHAVIOR DURING HINDBRAIN SEGMENTATION

2018 ◽  
Author(s):  
Adrià Voltes ◽  
Covadonga F Hevia ◽  
Chaitanya Dingare ◽  
Simone Calzolari ◽  
Javier Terriente ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Lineage ◽  
Tissue Growth ◽  
Specific Cell ◽  
Cell Behaviors ◽  
Mechanical Signals ◽  
Matrix Cell ◽  
Physical Cues

SUMMARYCells perceive their microenvironment through chemical and physical cues. However, how mechanical signals are interpreted during embryonic tissue deformation resulting in specific cell behaviors is largely unexplored. The Yap/Taz family of transcriptional co-activators has emerged as an important regulator of tissue growth and regeneration, responding to physical cues from the extracellular matrix, cell shape and actomyosin cytoskeleton. In this work, we unveiled the role of Yap/Taz-TEAD activity as sensor of mechanical signals in the regulation of the progenitor behavior of boundary cells during hindbrain compartmentalization. Monitoring in vivo Yap/Taz-activity during hindbrain segmentation we discovered that boundary cells respond to mechanical cues in a cell-autonomous manner through Yap/Taz-TEAD activity. Cell-lineage analysis revealed that Yap/Taz-TEAD boundary cells decrease their proliferative activity when Yap/Taz-TEAD ceased, preceding changes of cell fate: from proliferating progenitors to differentiated neurons. Functional experiments demonstrated the pivotal role of Yap/Taz-TEAD signaling in maintaining the progenitor features in the hindbrain boundary cell population.

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

2018 ◽  
Author(s):  
Douaa Mugahid ◽  
Marian Kalocsay ◽  
Scott Gruver ◽  
Leonid Peshkin ◽  
Marc W. Kirschner
Keyword(s):  
Cell Size ◽  
Mammalian Cells ◽  
Hippo Pathway ◽  
Growth Dynamics ◽  
Cell Number ◽  
Tissue Growth ◽  
Environment Control ◽  
Important Pathway ◽  
The Hippo Pathway

SummaryThe Hippo pathway, in which changes at the cell surface and in the extracellular environment control the activity of a downstream transcription factor, known as YAP in mammalian cells and Yorkie in Drosophila, has recently taken center-stage as perhaps the most important pathway in metazoans for controlling organ size. In intact tissues YAP activity is inhibited and the organ does not overgrow. When the organ is damaged, YAP is active and necessary for growth and regeneration to occur. The exact process by which YAP drives organ and tissue growth is not fully understood, although it is known to affect both cell size and cell number. Since cell size and proliferation are highly interdependent in many cultured cell studies, we investigated the role of YAP in the simultaneous regulation of both cell size and number. Our experiments reveal that YAP controls both cell size and cell proliferation by independent circuits, and that it affects each process non-cell autonomously via extracellular mediators. We identify that CYR61, a known secreted YAP target, is the major regulator of the non-cell autonomous increase in cell number, but does not affect cell size. The molecular identity of the non-cell autonomously acting mediator of cell size is yet to be identified.

Growth of tissues and organs

2021 ◽  
pp. 921-940
Keyword(s):  
Disease Progression ◽  
Cell Size ◽  
Gene Function ◽  
Molecular Mechanisms ◽  
Cell Number ◽  
Tissue Growth ◽  
Adenomatous Polyposis ◽  
Environmental Carcinogens ◽  
Mechanisms Of Formation

‘Growth of tissues and organs’ is an overview of the general principles of tissue growth due to changes in cell size (normal and pathological atrophy, hypertrophy including pathological conditions) or cell number (hyperplasia). Neoplasia, the formation of neoplasms (i.e. cancerous tumours), is considered, including naming conventions for neoplasms, their morphology, and molecular mechanisms of formation and growth, including gains in gene function (proto-oncogenes, such as p53 and adenomatous polyposis coli) and environmental carcinogens, and the role of metastasis in disease progression. Finally, their treatment by chemotherapy and radiobiology is discussed.

scholarly journals Vinculin recruitment to α-catenin halts the differentiation and maturation of enterocyte progenitors to maintain homeostasis of the Drosophila intestine.

2021 ◽  
Author(s):  
Jérôme Bohère ◽  
Buffy L Eldridge-Thomas ◽  
Golnar Kolahgar
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Number ◽  
Tissue Cell ◽  
Quiescent State ◽  
Tissue Stiffness ◽  
Cell Fate Decisions ◽  
Variable Content

Mechanisms communicating changes in tissue stiffness and size are particularly relevant in the intestine, because it is subject to constant mechanical stresses caused by peristalsis of its variable content. Using the Drosophila intestinal epithelium, we investigate the role of vinculin, one of the best characterised mechanoeffectors, which functions in both cadherin and integrin adhesion complexes. We discovered that vinculin regulates cell fate decisions, by preventing precocious activation and differentiation of intestinal progenitors into absorptive cells. It achieves this in concert with α-catenin at sites of cadherin adhesion, rather than as part of integrin function. Following asymmetric division of the stem cell into a stem cell and an enteroblast, the two cells initially remain connected by adherens junctions, where vinculin is required, only on the enteroblast side, to maintain the enteroblast in a quiescent state and inhibit further divisions of the stem cell. Removing vinculin increases enteroblast differentiation and numbers, resulting in an enlarged gut with improved ability to recover after starvation. Thus, mechanical regulation at the contact between stem cells and their progeny is used to control tissue cell number.

Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

2020 ◽  
Vol 48 (3) ◽  
pp. 1243-1253 ◽  
Author(s):  
Sukriti Kapoor ◽  
Sachin Kotak
Keyword(s):  
Symmetry Breaking ◽  
Cell Fate ◽  
Cell Cortex ◽  
Axis Formation ◽  
Aurora A Kinase ◽  
Aurora A ◽  
C Elegans ◽  
Cell Embryo ◽  
Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Helen Shiphrah Vethakanraj ◽  
Niveditha Chandrasekaran ◽  
Ashok Kumar Sekar
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Potential Role ◽  
Tumour Progression ◽  
Acid Ceramidase ◽  
The Core ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

scholarly journals EBF1 is expressed in pericytes and contributes to pericyte cell commitment

2021 ◽  
Author(s):  
Francesca Pagani ◽  
Elisa Tratta ◽  
Patrizia Dell’Era ◽  
Manuela Cominelli ◽  
Pietro Luigi Poliani
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
B Cell ◽  
Cell Fate ◽  
Early Stage ◽  
Cell Lineage ◽  
Cell Maturation ◽  
Cell Commitment

AbstractEarly B-cell factor-1 (EBF1) is a transcription factor with an important role in cell lineage specification and commitment during the early stage of cell maturation. Originally described during B-cell maturation, EBF1 was subsequently identified as a crucial molecule for proper cell fate commitment of mesenchymal stem cells into adipocytes, osteoblasts and muscle cells. In vessels, EBF1 expression and function have never been documented. Our data indicate that EBF1 is highly expressed in peri-endothelial cells in both tumor vessels and in physiological conditions. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS) analysis suggest that EBF1-expressing peri-endothelial cells represent bona fide pericytes and selectively express well-recognized markers employed in the identification of the pericyte phenotype (SMA, PDGFRβ, CD146, NG2). This observation was also confirmed in vitro in human placenta-derived pericytes and in human brain vascular pericytes (HBVP). Of note, in accord with the key role of EBF1 in the cell lineage commitment of mesenchymal stem cells, EBF1-silenced HBVP cells showed a significant reduction in PDGFRβ and CD146, but not CD90, a marker mostly associated with a prominent mesenchymal phenotype. Moreover, the expression levels of VEGF, angiopoietin-1, NG2 and TGF-β, cytokines produced by pericytes during angiogenesis and linked to their differentiation and activation, were also significantly reduced. Overall, the data suggest a functional role of EBF1 in the cell fate commitment toward the pericyte phenotype.

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