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Stochasticity of cellular differentiation

Avner Friedman, Mirosław Lachowicz, Urszula Ledzewicz, Monika Joanna Piotrowska, Zuzanna Szymanska
This volume was inspired by the topics presented at the international conference "Micro and Macro Systems in Life Sciences" which was held on Jun 8-12, 2015 in Będlewo, Poland. System biology is an approach which tries to understand how micro systems, at the molecular and cellular levels, affect macro systems such as organs, tissue and populations. Thus it is not surprising that a major theme of this volume evolves around cancer and its treatment. Articles on this topic include models for tumor induced angiogenesis, without and with delays, metastatic niche of the bone marrow, drug resistance and metronomic chemotherapy, and virotherapy of glioma...
February 1, 2017: Mathematical Biosciences and Engineering: MBE
Seyed Ali Madani Tonekaboni, Andrew Dhawan, Mohammad Kohandel
The cancer stem cell (CSC) hypothesis suggests that cancer stem cells proliferate via a hierarchical model of unidirectional differentiation. However, growing experimental evidence has advanced this hypothesis by introducing a bidirectional hierarchy, in which non-CSCs may dedifferentiate into CSCs. Various models have been developed enabling the incorporation of this plasticity within cancer cell populations, focusing on behaviour in the limit of a large number of cells. However, stochastic effects predominate in the limit of small numbers of cells, which correlates with biologically relevant assays such as the mammosphere formation assay (MFA)...
January 2017: Mathematical Biosciences
Marcos E Gaudiano, Tom Lenaerts, Jorge M Pacheco
Blood of mammals is composed of a variety of cells suspended in a fluid medium known as plasma. Hematopoiesis is the biological process of birth, replication and differentiation of blood cells. Despite of being essentially a stochastic phenomenon followed by a huge number of discrete entities, blood formation has naturally an associated continuous dynamics, because the cellular populations can - on average - easily be described by (e.g.) differential equations. This deterministic dynamics by no means contemplates some important stochastic aspects related to abnormal hematopoiesis, that are especially significant for studying certain blood cancer deceases...
December 2016: Mathematical Biosciences
Adriano Bonforti, Salva Duran-Nebreda, Raúl Montañez, Ricard Solé
Spatial self-organization emerges in distributed systems exhibiting local interactions when nonlinearities and the appropriate propagation of signals are at work. These kinds of phenomena can be modeled with different frameworks, typically cellular automata or reaction-diffusion systems. A different class of dynamical processes involves the correlated movement of agents over space, which can be mediated through chemotactic movement or minimization of cell-cell interaction energy. A classic example of the latter is given by the formation of spatially segregated assemblies when cells display differential adhesion...
October 2016: Chaos
Julia Franzen, Anne Zirkel, Jonathon Blake, Björn Rath, Vladimir Benes, Argyris Papantonis, Wolfgang Wagner
Replicative senescence has a major impact on function and integrity of cell preparations. This process is reflected by continuous DNA methylation (DNAm) changes at specific CpG dinucleotides in the course of in vitro culture, and such modifications can be used to estimate the state of cellular senescence for quality control of cell preparations. Still, it is unclear how senescence-associated DNAm changes are regulated and whether they occur simultaneously across a cell population. In this study, we analyzed global DNAm profiles of human mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) to demonstrate that senescence-associated DNAm changes are overall similar in these different cell types...
October 26, 2016: Aging Cell
Vera Schützhold, Jens Hahn, Katja Tummler, Edda Klipp
Lipid metabolism is essential for all major cell functions and has recently gained increasing attention in research and health studies. However, mathematical modeling by means of classical approaches such as stoichiometric networks and ordinary differential equation systems has not yet provided satisfactory insights, due to the complexity of lipid metabolism characterized by many different species with only slight differences and by promiscuous multifunctional enzymes. Here, we present an object-oriented stochastic model approach as a way to cope with the complex lipid metabolic network...
2016: Frontiers in Molecular Biosciences
Matthew Z Anderson, Allison M Porman, Na Wang, Eugenio Mancera, Denis Huang, Christina A Cuomo, Richard J Bennett
Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states...
October 2016: PLoS Genetics
Manuel Gunkel, Holger Erfle, Vytaute Starkuviene
The Golgi complex plays a central role in a number of diverse cellular processes, and numerous regulators that control these functions and/or morphology of the Golgi complex are known by now. Many of them were identified by large-scale experiments, such as RNAi-based screening. However, high-throughput experiments frequently provide only initial information that a particular protein might play a role in regulating structure and function of the Golgi complex. Multiple follow-up experiments are necessary to functionally characterize the selected hits...
2016: Methods in Molecular Biology
Sayuri K Hahl, Andreas Kremling
In the mathematical modeling of biochemical reactions, a convenient standard approach is to use ordinary differential equations (ODEs) that follow the law of mass action. However, this deterministic ansatz is based on simplifications; in particular, it neglects noise, which is inherent to biological processes. In contrast, the stochasticity of reactions is captured in detail by the discrete chemical master equation (CME). Therefore, the CME is frequently applied to mesoscopic systems, where copy numbers of involved components are small and random fluctuations are thus significant...
2016: Frontiers in Genetics
Shawal Spencer, Agustina Gugliotta, Natascha Gödecke, Hansjörg Hauser, Dagmar Wirth
Tumor cells display phenotypic plasticity and heterogeneity due to genetic and epigenetic variations which limit the predictability of therapeutic interventions. Chromatin modifications can arise stochastically but can also be a consequence of environmental influences such as the microenvironment of cancer cells. A better understanding of the impact and dynamics of epigenetic modulation at defined chromosomal sites is required to get access to the underlying mechanisms. We investigated the epigenetic modulations leading to cell-to-cell heterogeneity in a tumor cell line model...
August 20, 2016: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Arne Bittig, Adelinde Uhrmacher
Spatio-temporal dynamics of cellular processes can be simulated at different levels of detail, from (deterministic) partial differential equations via the spatial Stochastic Simulation algorithm to tracking Brownian trajectories of individual particles. We present a spatial simulation approach for multi-level rule-based models, which includes dynamically hierarchically nested cellular compartments and entities. Our approach ML-Space combines discrete compartmental dynamics, stochastic spatial approaches in discrete space, and particles moving in continuous space...
August 3, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Steffen Rulands, Benjamin D Simons
The coordination of cell proliferation and differentiation is central to the development and maintenance of tissues, while its dysregulation underlies the transition to diseased states. By combining lineage tracing with transcriptional profiling and marker-based assays, statistical methods are delivering insights into the dynamics of stem cells and their developmental precursors. These studies have provided evidence for molecular heterogeneity and fate priming, and have revealed a role for stochasticity in stem cell fate, refocusing the search for regulatory mechanisms...
December 2016: Current Opinion in Cell Biology
Zheng Sun, Maksim V Plikus, Natalia L Komarova
Homeostatic maintenance of tissues is orchestrated by well tuned networks of cellular signaling. Such networks regulate, in a stochastic manner, fates of all cells within the respective lineages. Processes such as symmetric and asymmetric divisions, differentiation, de-differentiation, and death have to be controlled in a dynamic fashion, such that the cell population is maintained at a stable equilibrium, has a sufficiently low level of stochastic variation, and is capable of responding efficiently to external damage...
July 2016: PLoS Computational Biology
Miguel Fdo Salazar, Paola Andrea Escalante Abril, María Verónica Velasco Vales, Celene Martínez Ruiz, Erick Gómez Apo, Laura G Chávez Macías
Haemangioblastomas are neoplasms of uncertain histogenesis with cellular and reticular variants advocated in current lore. Herein we describe an intriguing cerebellar specimen with unusual traits including spindle cell morphology and CD34 positivity. A thirty-nine-year old man had an infratentorial tumour discovered incidentally and resected three times. In all the instances, histopathological diagnosis was haemangioblastoma; nonetheless, he had neither physical stigmata nor family history of von Hippel-Lindau disease...
2016: Case Reports in Pathology
Hirotaka Matsumoto, Hisanori Kiryu
BACKGROUND: Single-cell technologies make it possible to quantify the comprehensive states of individual cells, and have the power to shed light on cellular differentiation in particular. Although several methods have been developed to fully analyze the single-cell expression data, there is still room for improvement in the analysis of differentiation. RESULTS: In this paper, we propose a novel method SCOUP to elucidate differentiation process. Unlike previous dimension reduction-based approaches, SCOUP describes the dynamics of gene expression throughout differentiation directly, including the degree of differentiation of a cell (in pseudo-time) and cell fate...
2016: BMC Bioinformatics
Nikolay Martyushenko, Sigurd Hagen Johansen, Cheol-Min Ghim, Eivind Almaas
BACKGROUND: Genetic switches are ubiquitous in nature, frequently associated with the control of cellular functions and developmental programs. In the realm of synthetic biology, it is of great interest to engineer genetic circuits that can change their mode of operation from monostable to bistable, or even to multistable, based on the experimental fine-tuning of readily accessible parameters. In order to successfully design robust, bistable synthetic circuits to be used as biomolecular probes, or understand modes of operation of such naturally occurring circuits, we must identify parameters that are key in determining their characteristics...
2016: BMC Systems Biology
Sarah Filippi, Chris P Barnes, Paul D W Kirk, Takamasa Kudo, Katsuyuki Kunida, Siobhan S McMahon, Takaho Tsuchiya, Takumi Wada, Shinya Kuroda, Michael P H Stumpf
Cellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signaling systems remain poorly understood. Here, we measure the dynamics of phosphorylated MEK and ERK across cell populations and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modeling framework to show that extrinsic noise, particularly that from upstream MEK, is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK...
June 14, 2016: Cell Reports
François Delavat, Sara Mitri, Serge Pelet, Jan Roelof van der Meer
Horizontal gene transfer is an important evolutionary mechanism for bacterial adaptation. However, given the typical low transfer frequencies in a bacterial population, little is known about the fate and interplay of donor cells and the mobilized DNA during transfer. Here we study transfer of an integrative and conjugative element (ICE) among individual live bacterial cells. ICEs are widely distributed mobile DNA elements that are different than plasmids because they reside silent in the host chromosome and are maintained through vertical descent...
14, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yuncheng Du, Hector M Budman, Thomas A Duever
Accurate automated quantitative analysis of living cells based on fluorescence microscopy images can be very useful for fast evaluation of experimental outcomes and cell culture protocols. In this work, an algorithm is developed for fast differentiation of normal and apoptotic viable Chinese hamster ovary (CHO) cells. For effective segmentation of cell images, a stochastic segmentation algorithm is developed by combining a generalized polynomial chaos expansion with a level set function-based segmentation algorithm...
June 2016: Microscopy and Microanalysis
Annapurna Vemu, Joseph Atherton, Jeffrey O Spector, Agnieszka Szyk, Carolyn A Moores, Antonina Roll-Mecak
Microtubules are polymers that cycle stochastically between polymerization and depolymerization, i.e. they exhibit "dynamic instability." This behavior is crucial for cell division, motility, and differentiation. Although studies in the last decade have made fundamental breakthroughs in our understanding of how cellular effectors modulate microtubule dynamics, analysis of the relationship between tubulin sequence, structure, and dynamics has been held back by a lack of dynamics measurements with and structural characterization of homogeneous isotypically pure engineered tubulin...
June 17, 2016: Journal of Biological Chemistry
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