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.

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

2021 ◽  
Author(s):  
Megan K. Franke ◽  
Adam L. MacLean
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Single Cells ◽  
System Modeling ◽  
Cell Communication ◽  
Internal Dynamic ◽  
Cell Fate Decision ◽  
Wide Range ◽  
Fate Decision ◽  
Cell Cell

The role of cell-cell communication in cell fate decision-making has not been well-characterized through a dynamical systems perspective. To do so, here we develop multiscale models that couple cell-cell communication with cell-internal gene regulatory network dynamics. This allows us to study the influence of external signaling on cell fate decision-making at the resolution of single cells. We study the granulocyte-monocyte vs. megakaryocyte-erythrocyte fate decision, dictated by the GATA1-PU.1 network, as an exemplary bistable cell fate system, modeling the cell-internal dynamic with ordinary differential equations and the cell-cell communication via a Poisson process. We show that, for a wide range of cell communication topologies, subtle changes in signaling can lead to dramatic changes in cell fate. We find that cell-cell coupling can explain how populations of heterogeneous cell types can arise. Analysis of intrinsic and extrinsic cell-cell communication noise demonstrates that noise alone can alter the cell fate decision-making boundaries. These results illustrate how external signals alter transcriptional dynamics, and provide insight into hematopoietic cell fate decision-making.

scholarly journals Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell fates in embryonic stem cells

2020 ◽  
Author(s):  
Dhruv Raina ◽  
Angel Stanoev ◽  
Azra Bahadori ◽  
Michelle Protzek ◽  
Aneta Koseska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Initial Conditions ◽  
Embryonic Stem ◽  
Cell Communication ◽  
Cell Types ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Cell Cell

AbstractDuring embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types need to be specified from homogeneous precursor cell populations. How this is achieved despite uncertainty in initial conditions in the precursor cells, and how proportions are re-established upon perturbations in the developing tissue is not known. Here we report the differentiation of robust proportions of epiblast- and primitive endoderm-like cells from a wide range of experimentally controlled initial conditions in mouse embryonic stem cells. We demonstrate both experimentally and theoretically that recursive cell-cell communication via FGF4 establishes a population-based mechanism that generates and maintains robust proportions of differentiated cell types. Furthermore, we show that cell-cell communication re-establishes heterogeneous cell identities following the isolation of one cell type. The generation and maintenance of robust cell fate proportions is a new function for FGF signaling that may extend to other cell fate decisions.

scholarly journals Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Chemical Signalling ◽  
Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

scholarly journals Variability in β-catenin pulse dynamics in a stochastic cell fate decision in C. elegans

2018 ◽  
Author(s):  
Jason R. Kroll ◽  
Jasonas Tsiaxiras ◽  
Jeroen S. van Zon
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Cell Fusion ◽  
Precursor Cell ◽  
Cell Fate Decision ◽  
Absolute Level ◽  
Cell Fate Decisions ◽  
Pulse Dynamics ◽  
Significant Variability ◽  
Fate Decision

AbstractDuring development, cell fate decisions are often highly stochastic, but with the frequency of the different possible fates tightly controlled. To understand how signaling networks control the cell fate frequency of such random decisions, we studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. Using time-lapse microscopy to measure the single-cell dynamics of two key inhibitors of cell fusion, the Hox gene LIN-39 and Wnt signaling through the β-catenin BAR-1, we uncovered significant variability in the dynamics of LIN-39 and BAR-1 levels. Most strikingly, we observed that BAR-1 accumulated in a single, 1-4 hour pulse at the time of the P3.p cell fate decision, with strong variability both in pulse slope and time of pulse onset. We found that the time of BAR-1 pulse onset was delayed relative to the time of cell fusion in mutants with low cell fusion frequency, linking BAR-1 pulse timing to cell fate outcome. Overall, a model emerged where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced. Our results highlight that timing of cell signaling dynamics, rather than its average level or amplitude, could play an instructive role in determining cell fate.Article summaryWe studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. We uncovered significant variability in the dynamics of LIN-39/Hox and BAR-1/β-catenin levels, two key inhibitors of cell fusion. Surprisingly, we observed that BAR-1 accumulated in a 1-4 hour pulse at the time of the P3.p cell fate decision, with variable pulse slope and time of pulse onset. Our work suggests a model where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced.

Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 135 (3) ◽  
pp. 765-783 ◽  
Author(s):  
M Sundaram ◽  
I Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Gene Dosage ◽  
Egg Laying ◽  
Loss Of Function ◽  
Cell Fate Decision ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Suppressor Mutations ◽  
Fate Decision

Abstract The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor which mediates cell-cell interactions required to specify certain cell fates. Reversion of the egg-laying defective phenotype caused by a hypomorphic lin-12 allele identified rare extragenic suppressor mutations in five genes, sel-1, sel-9, sel-10, sel-11 and sel(ar40) (sel = suppressor and/or enhancer of lin-12). Mutations in each of these sel genes suppress defects associated with reduced lin-12 activity, and enhance at least one defect associated with elevated lin-12 activity. None of the sel mutations cause any obvious phenotype in a wild-type background. Gene dosage experiments suggest that sel-1 and sel(ar40) mutations are reduction-of-function mutations, while sel-9 and sel-11 mutations are gain-of-function mutations. sel-1, sel-9, sel-11 and sel(ar40) mutations do not suppress amorphic lin-12 alleles, while sel-10 mutations are able to bypass partially the requirement for lin-12 activity in at least one cell fate decision. sel-1, sel-9, sel-10, sel-11 and sel(ar40) mutations are also able to suppress the maternal-effect lethality caused by a partial loss-of-function allele of glp-1, a gene that is both structurally and functionally related to lin-12. These sel genes may therefore function in both lin-12 and glp-1 mediated cell fate decisions.

scholarly journals Accessible chromatin reveals regulatory mechanisms underlying cell fate decisions during early embryogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tongqiang Fan ◽  
Youjun Huang
Keyword(s):  
Cell Fate ◽  
Chromatin Accessibility ◽  
Early Embryogenesis ◽  
Regulatory Sequences ◽  
Cell Fate Decision ◽  
Joint Research ◽  
Cell Fate Decisions ◽  
Fate Decision ◽  
Multiple Species ◽  
Accessible Chromatin

AbstractThis study was conducted to investigate epigenetic landscape across multiple species and identify transcription factors (TFs) and their roles in controlling cell fate decision events during early embryogenesis. We made a comprehensively joint-research of chromatin accessibility of five species during embryogenesis by integration of ATAC-seq and RNA-seq datasets. Regulatory roles of candidate early embryonic TFs were investigated. Widespread accessible chromatin in early embryos overlapped with putative cis-regulatory sequences. Sets of cell-fate-determining TFs were identified. YOX1, a key cell cycle regulator, were found to homologous to clusters of TFs that are involved in neuron and epidermal cell-fate determination. Our research provides an intriguing insight into evolution of cell-fate decision during early embryogenesis among organisms.

scholarly journals Quantifying Waddington landscapes and paths of non-adiabatic cell fate decisions for differentiation, reprogramming and transdifferentiation

2013 ◽  
Vol 10 (89) ◽  
pp. 20130787 ◽  
Author(s):  
Chunhe Li ◽  
Jin Wang
Keyword(s):  
Decision Making ◽  
Stem Cell ◽  
Cell Fate ◽  
Intermediate State ◽  
Regulatory Networks ◽  
Experimental Studies ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Decision Making Processes ◽  
Fate Decision

Cellular differentiation, reprogramming and transdifferentiation are determined by underlying gene regulatory networks. Non-adiabatic regulation via slow binding/unbinding to the gene can be important in these cell fate decision-making processes. Based on a stem cell core gene network, we uncovered the stem cell developmental landscape. As the binding/unbinding speed decreases, the landscape topography changes from bistable attractors of stem and differentiated states to more attractors of stem and other different cell states as well as substates. Non-adiabaticity leads to more differentiated cell types and provides a natural explanation for the heterogeneity observed in the experiments. We quantified Waddington landscapes with two possible cell fate decision mechanisms by changing the regulation strength or regulation timescale (non-adiabaticity). Transition rates correlate with landscape topography through barrier heights between different states and quantitatively determine global stability. We found the optimal speeds of these cell fate decision-making processes. We quantified biological paths and predict that differentiation and reprogramming go through an intermediate state (IM1), whereas transdifferentiation goes through another intermediate state (IM2). Some predictions are confirmed by recent experimental studies.

scholarly journals Investigating higher order interactions in single cell data with scHOT

2019 ◽  
Author(s):  
Shila Ghazanfar ◽  
Yingxin Lin ◽  
Xianbin Su ◽  
David M. Lin ◽  
Ellis Patrick ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Expression Profiles ◽  
Order Effect ◽  
Higher Order ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Novel Approach ◽  
Fate Decision ◽  
Cell Data

ABSTRACTSingle-cell RNA-sequencing has transformed our ability to examine cell fate choice. For example, in the context of development and differentiation, computational ordering of cells along ‘pseudotime’ enables the expression profiles of individual genes, including key transcription factors, to be examined at fine scale temporal resolution. However, while cell fate decisions are typically marked by profound changes in expression, many such changes are observed in genes downstream of the initial cell fate decision. By contrast, the genes directly involved in the cell fate decision process are likely to interact in subtle ways, potentially resulting in observed changes in patterns of correlation and variation rather than mean expression prior to cell fate commitment. Herein, we describe a novel approach, scHOT – single cell Higher Order Testing - which provides a flexible and statistically robust framework for identifying changes in higher order interactions among genes. scHOT is general and modular in nature, can be run in multiple data contexts such as along a continuous trajectory, between discrete groups, and over spatial orientations; as well as accommodate any higher order measurement such as variability or correlation. We demonstrate the utility of scHOT by studying embryonic development of the liver, where we find coordinated changes in higher order interactions of programs related to differentiation and liver function. We also demonstrate its ability to find subtle changes in gene-gene correlation patterns across space using spatially-resolved expression data from the mouse olfactory bulb. scHOT meaningfully adds to first order effect testing, such as differential expression, and provides a framework for interrogating higher order interactions from single cell data.

scholarly journals Modular HUWE1 architecture serves as hub for degradation of cell-fate decision factors

2020 ◽  
Author(s):  
Moritz Hunkeler ◽  
Cyrus Y. Jin ◽  
Michelle W. Ma ◽  
Daan Overwijn ◽  
Julie K. Monda ◽  
...  
Keyword(s):  
Cell Fate ◽  
Three Dimensional ◽  
Cellular Stress Response ◽  
Cell Fate Decision ◽  
Decision Factors ◽  
Link Functions ◽  
Wide Range ◽  
Essential Enzyme ◽  
Fate Decision ◽  
Molecular Picture

SummaryHECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors including Mcl1, p53, DDIT4, and Myc. As a step toward understanding regulation of HUWE1 engagement with its diverse substrates, we present here the cryo-EM structure of HUWE1, offering a first complete molecular picture of a HECT ubiquitin ligase. The ~4400 amino acid residue polypeptide forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. This modularity enables HUWE1 to target a wide range of substrates for destruction. The locations of human mutations associated with severe neurodevelopmental disorders link functions of this essential enzyme with its three-dimensional organization.

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