scholarly journals Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julien Hurbain ◽  
Darka Labavić ◽  
Quentin Thommen ◽  
Benjamin Pfeuty
Keyword(s):  
Cell Fate ◽  
Stochastic Dynamics ◽  
Biochemical Networks ◽  
Stochastic Bifurcation ◽  
Modeling Framework ◽  
Life And Death ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Adaptation Response ◽  
The Impact

Abstract Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

scholarly journals Identifying inhibitors of epithelial-mesenchymal plasticity using a network topology based approach

2019 ◽  
Author(s):  
Kishore Hari ◽  
Burhanuddin Sabuwala ◽  
Balaram Vishnu Subramani ◽  
Caterina La Porta ◽  
Stefano Zapperi ◽  
...  
Keyword(s):  
Phenotypic Plasticity ◽  
Cancer Cells ◽  
Network Topology ◽  
Positive Feedback ◽  
Regulatory Networks ◽  
Therapy Resistance ◽  
Feedback Loops ◽  
Biochemical Networks ◽  
Modeling Framework ◽  
Wide Range

Metastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis switch dynamically between different phenotypes, enabling them to adapt to harsh challenges such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial-Mesenchymal Plasticity (EMP) - an important arm of phenotypic plasticity - through two different mathematical modeling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modeling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability of exhibit phenotypic plasticity positively correlates with the number of positive feedback loops. These results pave a way towards an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis - by reducing the number of positive feedback loops .

scholarly journals Quantifying the Stability of Coupled Genetic and Epigenetic Switches With Variational Methods

2021 ◽  
Vol 11 ◽  
Author(s):  
Amogh Sood ◽  
Bin Zhang
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Histone Modifications ◽  
Regulatory Networks ◽  
Variational Principles ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Fate Decisions ◽  
The Impact

The Waddington landscape provides an intuitive metaphor to view development as a ball rolling down the hill, with distinct phenotypes as basins and differentiation pathways as valleys. Since, at a molecular level, cell differentiation arises from interactions among the genes, a mathematical definition for the Waddington landscape can, in principle, be obtained by studying the gene regulatory networks. For eukaryotes, gene regulation is inextricably and intimately linked to histone modifications. However, the impact of such modifications on both landscape topography and stability of attractor states is not fully understood. In this work, we introduced a minimal kinetic model for gene regulation that combines the impact of both histone modifications and transcription factors. We further developed an approximation scheme based on variational principles to solve the corresponding master equation in a second quantized framework. By analyzing the steady-state solutions at various parameter regimes, we found that histone modification kinetics can significantly alter the behavior of a genetic network, resulting in qualitative changes in gene expression profiles. The emerging epigenetic landscape captures the delicate interplay between transcription factors and histone modifications in driving cell-fate decisions.

scholarly journals The Impact of Epigenetic Signatures on Amniotic Fluid Stem Cell Fate

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Daniela Di Tizio ◽  
Alessandra Di Serafino ◽  
Prabin Upadhyaya ◽  
Luca Sorino ◽  
Liborio Stuppia ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Amniotic Fluid ◽  
Cell Fate ◽  
Histone Modifications ◽  
Current Evidence ◽  
Cell Fate Decisions ◽  
Small Noncoding Rnas ◽  
Tight Correlation ◽  
The Impact

Epigenetic modifications play a significant role in determining the fate of stem cells and in directing the differentiation into multiple lineages. Current evidence indicates that mechanisms involved in chromatin regulation are essential for maintaining stable cell identities. There is a tight correlation among DNA methylation, histone modifications, and small noncoding RNAs during the epigenetic control of stem cells’ differentiation; however, to date, the precise mechanism is still not clear. In this context, amniotic fluid stem cells (AFSCs) represent an interesting model due to their unique features and the possible advantages of their use in regenerative medicine. Recent studies have elucidated epigenetic profiles involved in AFSCs’ lineage commitment and differentiation. In order to use these cells effectively for therapeutic purposes, it is necessary to understand the basis of multiple-lineage potential and elaborate in detail how cell fate decisions are made and memorized. The present review summarizes the most recent findings on epigenetic mechanisms of AFSCs with a focus on DNA methylation, histone modifications, and microRNAs (miRNAs) and addresses how their unique signatures contribute to lineage-specific differentiation.

Phagocyte NADPH oxidase and specific immunity

2015 ◽  
Vol 128 (10) ◽  
pp. 635-648 ◽  
Author(s):  
Julien Cachat ◽  
Christine Deffert ◽  
Stephanie Hugues ◽  
Karl-Heinz Krause
Keyword(s):  
Dendritic Cells ◽  
Nadph Oxidase ◽  
Cell Fate ◽  
B Lymphocytes ◽  
Antigen Processing ◽  
Ros Generation ◽  
Cell Fate Decisions ◽  
Specific Immunity ◽  
Phagocyte Nadph Oxidase ◽  
The Impact

The phagocyte NADPH oxidase NOX2 produces reactive oxygen species (ROS) and is a well-known player in host defence. However, there is also increasing evidence for a regulatory role of NOX2 in adaptive immunity. Deficiency in phagocyte NADPH oxidase causes chronic granulomatous disease (CGD) in humans, a condition that can also be studied in CGD mice. Clinical observations in CGD patients suggest a higher susceptibility to autoimmune diseases, in particular lupus, idiopathic thrombocytopenic purpura and rheumatoid arthritis. In mice, a strong correlation exists between a polymorphism in a NOX2 subunit and the development of autoimmune arthritis. NOX2 deficiency in mice also favours lupus development. Both CGD patients and CGD mice exhibit increased levels of immunoglobulins, including autoantibodies. Despite these phenotypes suggesting a role for NOX2 in specific immunity, mechanistic explanations for the typical increase of CGD in autoimmune disease and antibody levels are still preliminary. NOX2-dependent ROS generation is well documented for dendritic cells and B-lymphocytes. It is unclear whether T-lymphocytes produce ROS themselves or whether they are exposed to ROS derived from dendritic cells during the process of antigen presentation. ROS are signalling molecules in virtually any cell type, including T- and B-lymphocytes. However, knowledge about the impact of ROS-dependent signalling on T- and B-lymphocyte phenotype and response is still limited. ROS might contribute to Th1/Th2/Th17 cell fate decisions during T-lymphocyte activation and might enhance immunoglobulin production by B-lymphocytes. In dendritic cells, NOX2-derived ROS might be important for antigen processing and cell activation.

scholarly journals Oxygen-generated spatial distribution of cell population links to p53 status

2019 ◽  
Author(s):  
Shashank Taxak ◽  
Uttam Pati
Keyword(s):  
Spatial Distribution ◽  
Cell Fate ◽  
Cell Population ◽  
Oxygen Sensor ◽  
Dynamic State ◽  
Specific Cell ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Wild Type P53

ABSTRACTLow oxygen induces wild type p53 inactivation and selects for mutant-like p53 phenotypes for aggressive tumor growth. Recently, we have shown wild type p53 as a cellular oxygen-sensor that operates in switch-like fashion to transform its characters of a tumor suppressor or promoter in a gradient of hypoxia. However, it is unclear how hypoxic tumors select for wild type p53 phenotypes for oxygen-sensitive responses. Here, we show that oxygen-generated spatial distribution of the cell population induces p53 phenotype-specific survival or death. We have found that a dynamic state of spatial scatters or clustering patterns of cell populations favor the survival of wild type more than the mutant phenotypes in a wide range of oxygen fluctuation by affecting p53 subcellular localization. Our results demonstrate how spatial distribution could function to establish wild type p53-mediated oxygen sensing and cell fate decisions in a cell population with heterogeneous p53 allele status. We anticipate that such behavior of cells in a gradient of oxygen can be utilized by the hypoxic tumors to maintain distinct p53 alleles and determine the release and metastasis of single or clustered circulating tumor cells (CTCs).Summary sentenceOxygen variation results in p53 phenotype-specific cell fate via the spatial distribution pattern of the cell population

scholarly journals A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

Development ◽  
2021 ◽  
Vol 148 (24) ◽  
Author(s):  
Megan K. Rommelfanger ◽  
Adam L. MacLean
Keyword(s):  
Cell Fate ◽  
Cell Communication ◽  
Communication Model ◽  
Cell Fate Decision ◽  
Cell Coupling ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Fate Decision ◽  
Cell Cell

ABSTRACT Cells do not make fate decisions independently. Arguably, every cell-fate decision occurs in response to environmental signals. In many cases, cell-cell communication alters the dynamics of the internal gene regulatory network of a cell to initiate cell-fate transitions, yet models rarely take this into account. Here, we have developed a multiscale perspective to study the granulocyte-monocyte versus megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network: a classical example of a bistable cell-fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell-fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell-fate decision-making system. This article has an associated ‘The people behind the papers’ interview.

Probabilistic Response and Stochastic Bifurcation in a Turbulent Swirling Flow

2019 ◽  
Vol 14 (11) ◽  
Author(s):  
Xiaole Yue ◽  
Yanyan Wang ◽  
Qun Han ◽  
Yong Xu ◽  
Wei Xu
Keyword(s):  
Stochastic Dynamics ◽  
Swirling Flow ◽  
Gaussian Approximation ◽  
Stable State ◽  
Stochastic Bifurcation ◽  
Dimensional System ◽  
Stable States ◽  
Generalized Cell Mapping ◽  
Wide Range ◽  
Storage Problem

Abstract Stochastic dynamics in a turbulent swirling flow are reported in this paper via the probability density functions (PDFs) of responses with the generalized cell mapping (GCM) method. Based on the short-time Gaussian approximation (STGA) procedure, the influence generated by the time average and the amplitude of the fluctuation to the turbulent flow on the probabilistic responses are demonstrated. We observe that the shapes of the steady-state PDFs change from two peaks to the single peak with the change of system parameters, indicating that the rotation to shear ratio will change from two stable states into one stable state, while the torque difference of the propellers in the von-Karman turbulence experimental setup becomes large or changes in a wide range. That is to say, the stochastic P-bifurcation phenomena occur. The evolutionary mechanism of the transient response is revealed with the global portraits. Furthermore, the idea of block matrix is devoted to solving the storage problem due to the amount of image cells for the STGA procedure in high dimensional system. Monte Carlo (MC) simulations are in good agreement with the proposed strategy.

Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 1960-1967 ◽  
Author(s):  
Francis N. Karanu ◽  
Barbara Murdoch ◽  
Tomoyuki Miyabayashi ◽  
Mitsuhara Ohno ◽  
Masahide Koremoto ◽  
...  
Keyword(s):  
Cell Fate ◽  
Hematopoietic Cells ◽  
Functional Roles ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Deficient Mice

Delta-mediated Notch signaling controls cell fate decisions during invertebrate and murine development. However, in the human, functional roles for Delta have yet to be described. This study reports the characterization of Delta-1 and Delta-4 in the human. Human Delta-4 was found to be expressed in a wide range of adult and fetal tissues, including sites of hematopoiesis. Subsets of immature hematopoietic cells, along with stromal and endothelial cells that support hematopoiesis, were shown to express Notch and both Delta-1 and Delta-4. Soluble forms of human Delta-1 (hDelta-1) and hDelta-4 proteins were able to augment the proliferation of primitive human hematopoietic progenitors in vitro. Intravenous transplantation of treated cultures into immune-deficient mice revealed that hDelta-1 is capable of expanding pluripotent human hematopoietic repopulating cells detected in vivo. This study provides the first evidence for a role of Delta ligands as a mitogenic regulator of primitive hematopoietic cells in the human.

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