scholarly journals Close to optimal cell sensing ensures the robustness of tissue differentiation process: the avian photoreceptor mosaic case

2021 ◽  
Author(s):  
Arnab Barua ◽  
Alireza Beygi ◽  
Haralampos Hatzikirou
Keyword(s):  
Cell Fate ◽  
Cell Metabolism ◽  
Explanatory Power ◽  
Spatial Order ◽  
Cell Level ◽  
Stochastic Thermodynamics ◽  
Cell Fate Decisions ◽  
Model Predictions ◽  
Sensing Radius ◽  
Photoreceptor Mosaic

AbstractThe way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility) but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP can predict the cone color spatial distribution in the avian retina and, at the same time, suggest that such a spatial pattern is associated with quasi-optimal cell sensing. By means of the stochastic thermodynamics formalism, we find out that thermodynamic robustness of differentiated tissues depends on cell metabolism and cell sensing properties. In turn, we calculate the limits of the cell sensing radius that ensure the robustness of differentiated tissue spatial order. Finally, we further constrain our model predictions to the avian photoreceptor mosaic.

scholarly journals Close to Optimal Cell Sensing Ensures the Robustness of Tissue Differentiation Process: The Avian Photoreceptor Mosaic Case

Entropy ◽  
2021 ◽  
Vol 23 (7) ◽  
pp. 867
Author(s):  
Arnab Barua ◽  
Alireza Beygi ◽  
Haralampos Hatzikirou
Keyword(s):  
Cell Fate ◽  
Cell Metabolism ◽  
Explanatory Power ◽  
Spatial Order ◽  
Cell Level ◽  
Stochastic Thermodynamics ◽  
Cell Fate Decisions ◽  
Model Predictions ◽  
Sensing Radius ◽  
Photoreceptor Mosaic

The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility), but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP can predict the cone color spatial distribution in the avian retina and, at the same time, suggest that such a spatial pattern is associated with quasi-optimal cell sensing. By means of the stochastic thermodynamics formalism, we find out that thermodynamic robustness of differentiated tissues depends on cell metabolism and cell sensing properties. In turn, we calculate the limits of the cell sensing radius that ensure the robustness of differentiated tissue spatial order. Finally, we further constrain our model predictions to the avian photoreceptor mosaic.

scholarly journals Metabolic Control and Systems Immunology in Blood Cell Development

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-43-SCI-43
Author(s):  
Hongbo Chi
Keyword(s):  
Cell Fate ◽  
Conflicts Of Interest ◽  
Cell Metabolism ◽  
Cell Development ◽  
Dynamic Regulation ◽  
Cell Fate Decisions ◽  
Systems Immunology ◽  
Mtorc1 Signaling ◽  
One Carbon Metabolism ◽  
And Function

Coordination of metabolic programs with cell fate decisions is a fundamental determinant of hematopoietic cell development and function. Hematopoietic cells at different developmental and activation stages exhibit distinct metabolic signatures. Emerging evidence further highlights the interplay between cell signaling and metabolic programming in these processes. We found that myelopoiesis, including the differentiation of monocytes, macrophages and dendritic cells (DCs), required mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving glycolysis and sterol biosynthesis after M-CSF stimulation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Moreover, we found that differentiation of DCs from bone marrow precursors was associated with dynamic regulation of mTORC1 signaling and cell metabolism. Either reduced or excessive mTORC1 activity was detrimental to DC development, associated with impaired regulation of cell metabolism. Interestingly, in contrast to the obligatory role of mTORC1 in monocyte and DC development, mTORC2 function was dispensable in these processes. Our results demonstrate that the interplay between mTORC1 signaling and bioenergetic and biosynthetic activities constitutes key metabolic checkpoints to orchestrate myelopoiesis. We are currently applying systems immunology approaches to explore metabolic signaling in myelopoiesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 513 ◽  
Author(s):  
Yu Muta ◽  
Michiyuki Matsuda ◽  
Masamichi Imajo
Keyword(s):  
Cell Fate ◽  
Cellular Responses ◽  
Erk Signaling ◽  
Biological Processes ◽  
Cell Level ◽  
Erk Activation ◽  
Cell Fate Decisions ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Erk Activity

The extracellular signal-regulated kinase (ERK) signaling pathway regulates a variety of biological processes including cell proliferation, survival, and differentiation. Since ERK activation promotes proliferation of many types of cells, its deregulated/constitutive activation is among general mechanisms for cancer. Recent advances in bioimaging techniques have enabled to visualize ERK activity in real-time at the single-cell level. Emerging evidence from such approaches suggests unexpectedly complex spatiotemporal dynamics of ERK activity in living cells and animals and their crucial roles in determining cellular responses. In this review, we discuss how ERK activity dynamics are regulated and how they affect biological processes including cell fate decisions, cell migration, embryonic development, tissue homeostasis, and tumorigenesis.

scholarly journals Revealing cell fate decisions during reprogramming by scRNA-seq

2020 ◽  
Vol 145 ◽  
pp. 01033
Author(s):  
Yu Liang
Keyword(s):  
Small Molecules ◽  
Single Cell ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Rapid Development ◽  
Underlying Mechanism ◽  
Cellular Heterogeneity ◽  
Cell Level ◽  
Cell Fate Decisions ◽  
Cell Fate Conversion

Single-cell RNA sequencing (scRNA-seq) technologies serve as powerful tools to dissect cellular heterogeneity comprehensively. With the rapid development of scRNA-seq, many previously unsolved questions were answered by using scRNA-seq. Cell reprogramming allows to reprogram the somatic cell into pluripotent stem cells by specific transcription factors or small molecules. However, the underlying mechanism for the reprogramming progress remains unclear in some aspects for it is a highly heterogeneous process. By using scRNA-seq, it is of great value for better understanding the mechanism of reprogramming process by analyzing cell fate conversion at single-cell level. In this review, we will introduce the methods of scRNA-seq and generation of iPSCs by reprogramming, and summarize the main researches that revealing reprogramming mechanism with the use scRNA-seq.

scholarly journals Deletion of Irf4 in T Cells Suppressed Autoimmune Uveitis and Dysregulated Transcriptional Programs Linked to CD4+ T Cell Differentiation and Metabolism

2021 ◽  
Vol 22 (5) ◽  
pp. 2775
Author(s):  
Minkyung Kang ◽  
Hyun-Su Lee ◽  
Jin Kyeong Choi ◽  
Cheng-Rong Yu ◽  
Charles E. Egwuagu
Keyword(s):  
T Cells ◽  
Cell Fate ◽  
B Lymphocyte ◽  
Synergistic Effects ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Lymphoid Tissues ◽  
Autoimmune Uveitis ◽  
Cell Fate Decisions ◽  
Proinflammatory Responses

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.

scholarly journals Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscape

NAR Cancer ◽  
2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Matías M Falco ◽  
María Peña-Chilet ◽  
Carlos Loucera ◽  
Marta R Hidalgo ◽  
Joaquín Dopazo
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Large Degree ◽  
Mechanistic Modeling ◽  
Therapeutic Interventions ◽  
Single Cell Level ◽  
Cell Level ◽  
Cell Fate Decisions ◽  
Cancer Hallmarks ◽  
Definition Of

Abstract Single-cell RNA sequencing is revealing an unexpectedly large degree of heterogeneity in gene expression levels across cell populations. However, little is known on the functional consequences of this heterogeneity and the contribution of individual cell fate decisions to the collective behavior of the tissues these cells are part of. Here, we use mechanistic modeling of signaling circuits, which reveals a complex functional landscape at single-cell level. Different clusters of neoplastic glioblastoma cells have been defined according to their differences in signaling circuit activity profiles triggering specific cancer hallmarks, which suggest different functional strategies with distinct degrees of aggressiveness. Moreover, mechanistic modeling of effects of targeted drug inhibitions at single-cell level revealed, how in some cells, the substitution of VEGFA, the target of bevacizumab, by other expressed proteins, like PDGFD, KITLG and FGF2, keeps the VEGF pathway active, insensitive to the VEGFA inhibition by the drug. Here, we describe for the first time mechanisms that individual cells use to avoid the effect of a targeted therapy, providing an explanation for the innate resistance to the treatment displayed by some cells. Our results suggest that mechanistic modeling could become an important asset for the definition of personalized therapeutic interventions.

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