The electronic crystal ball: predicting cell fate from time-lapse data

2010 ◽  
Vol 7 (3) ◽  
pp. 190-191 ◽  
Author(s):  
Timm Schroeder
Keyword(s):  
Cell Fate ◽  
Time Lapse ◽  
Crystal Ball ◽  
Electronic Crystal

scholarly journals A role for the fusogen eff-1 in epidermal stem cell number robustness in Caenorhabditis elegans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sneha L. Koneru ◽  
Fu Xiang Quah ◽  
Ritobrata Ghose ◽  
Mark Hintze ◽  
Nicola Gritti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Single Molecule ◽  
Phenotypic Variability ◽  
Low Frequency ◽  
Time Lapse ◽  
Cell Number ◽  
Seam Cell ◽  
Neuronal Tissues

AbstractDevelopmental patterning in Caenorhabditis elegans is known to proceed in a highly stereotypical manner, which raises the question of how developmental robustness is achieved despite the inevitable stochastic noise. We focus here on a population of epidermal cells, the seam cells, which show stem cell-like behaviour and divide symmetrically and asymmetrically over post-embryonic development to generate epidermal and neuronal tissues. We have conducted a mutagenesis screen to identify mutants that introduce phenotypic variability in the normally invariant seam cell population. We report here that a null mutation in the fusogen eff-1 increases seam cell number variability. Using time-lapse microscopy and single molecule fluorescence hybridisation, we find that seam cell division and differentiation patterns are mostly unperturbed in eff-1 mutants, indicating that cell fusion is uncoupled from the cell differentiation programme. Nevertheless, seam cell losses due to the inappropriate differentiation of both daughter cells following division, as well as seam cell gains through symmetric divisions towards the seam cell fate were observed at low frequency. We show that these stochastic errors likely arise through accumulation of defects interrupting the continuity of the seam and changing seam cell shape, highlighting the role of tissue homeostasis in suppressing phenotypic variability during development.

scholarly journals Antagonizing the spindle assembly checkpoint silencing enhances paclitaxel and Navitoclax-mediated apoptosis with distinct mechanistic

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Bruno Sarmento ◽  
Hassan Bousbaa
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Time Lapse ◽  
Antimitotic Drugs ◽  
Mitotic Slippage ◽  
Mitotic Death ◽  
Chronic Activation

AbstractAntimitotic drugs arrest cells in mitosis through chronic activation of the spindle assembly checkpoint (SAC), leading to cell death. However, drug-treated cancer cells can escape death by undergoing mitotic slippage, due to premature mitotic exit. Therefore, overcoming slippage issue is a promising chemotherapeutic strategy to improve the effectiveness of antimitotics. Here, we antagonized SAC silencing by knocking down the MAD2-binding protein p31comet, to delay mitotic slippage, and tracked cancer cells treated with the antimitotic drug paclitaxel, over 3 days live-cell time-lapse analysis. We found that in the absence of p31comet, the duration of mitotic block was increased in cells challenged with nanomolar concentrations of paclitaxel, leading to an additive effects in terms of cell death which was predominantly anticipated during the first mitosis. As accumulation of an apoptotic signal was suggested to prevent mitotic slippage, when we challenged p31comet-depleted mitotic-arrested cells with the apoptosis potentiator Navitoclax (previously called ABT-263), cell fate was shifted to accelerated post-mitotic death. We conclude that inhibition of SAC silencing is critical for enhancing the lethality of antimitotic drugs as well as that of therapeutic apoptosis-inducing small molecules, with distinct mechanisms. The study highlights the potential of p31comet as a target for antimitotic therapies.

scholarly journals Label free, quantitative single-cell fate tracking of time-lapse movies

MethodsX ◽  
2019 ◽  
Vol 6 ◽  
pp. 2468-2475 ◽  
Author(s):  
C. Elizabeth Caldon ◽  
Andrew Burgess
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Time Lapse ◽  
Label Free ◽  
Cell Fate Tracking

scholarly journals In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate

2017 ◽  
Vol 215 (1) ◽  
pp. 233-248 ◽  
Author(s):  
Christina Eich ◽  
Jochen Arlt ◽  
Chris S. Vink ◽  
Parham Solaimani Kartalaei ◽  
Polynikis Kaimakis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Single Cell Analysis ◽  
Single Cells ◽  
Time Lapse ◽  
Hematopoietic Stem ◽  
And Function ◽  
In Cells

Cell fate is established through coordinated gene expression programs in individual cells. Regulatory networks that include the Gata2 transcription factor play central roles in hematopoietic fate establishment. Although Gata2 is essential to the embryonic development and function of hematopoietic stem cells that form the adult hierarchy, little is known about the in vivo expression dynamics of Gata2 in single cells. Here, we examine Gata2 expression in single aortic cells as they establish hematopoietic fate in Gata2Venus mouse embryos. Time-lapse imaging reveals rapid pulsatile level changes in Gata2 reporter expression in cells undergoing endothelial-to-hematopoietic transition. Moreover, Gata2 reporter pulsatile expression is dramatically altered in Gata2+/− aortic cells, which undergo fewer transitions and are reduced in hematopoietic potential. Our novel finding of dynamic pulsatile expression of Gata2 suggests a highly unstable genetic state in single cells concomitant with their transition to hematopoietic fate. This reinforces the notion that threshold levels of Gata2 influence fate establishment and has implications for transcription factor–related hematologic dysfunctions.

scholarly journals Epigenetic Modification Affecting Expression of Cell Polarity and Cell Fate Genes to Regulate Lineage Specification in the Early Mouse Embryo

2010 ◽  
Vol 21 (15) ◽  
pp. 2649-2660 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Cell Fate ◽  
Cell Polarity ◽  
Mouse Embryo ◽  
Inner Cell Mass ◽  
Epigenetic Modification ◽  
Cell Mass ◽  
Time Lapse ◽  
Cell Polarization ◽  
Asymmetric Divisions

Formation of inner and outer cells of the mouse embryo distinguishes pluripotent inner cell mass (ICM) from differentiating trophectoderm (TE). Carm1, which methylates histone H3R17 and R26, directs cells to ICM rather that TE. To understand the mechanism by which this epigenetic modification directs cell fate, we generated embryos with in vivo–labeled cells of different Carm1 levels, using time-lapse imaging to reveal dynamics of their behavior, and related this to cell polarization. This shows that Carm1 affects cell fate by promoting asymmetric divisions, that direct one daughter cell inside, and cell engulfment, where neighboring cells with lower Carm1 levels compete for outside positions. This is associated with changes to the expression pattern and spatial distribution of cell polarity proteins: Cells with higher Carm1 levels show reduced expression and apical localization of Par3 and a dramatic increase in expression of PKCII, antagonist of the apical protein aPKC. Expression and basolateral localization of the mouse Par1 homologue, EMK1, increases concomitantly. Increased Carm1 also reduces Cdx2 expression, a transcription factor key for TE differentiation. These results demonstrate how the extent of a specific epigenetic modification could affect expression of cell polarity and fate-determining genes to ensure lineage allocation in the mouse embryo.

scholarly journals Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment

2017 ◽  
Author(s):  
Alice Moussy ◽  
Jérémie Cosette ◽  
Romuald Parmentier ◽  
Cindy da Silva ◽  
Guillaume Corre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Single Cell ◽  
Cell Fate ◽  
Morphological Changes ◽  
Gene Expression Pattern ◽  
Time Lapse ◽  
Dynamic Nature ◽  
Transcriptional Changes ◽  
Fate Decision

AbstractIndividual cells take lineage commitment decisions in a way that is not necessarily uniform. We address this issue by characterizing transcriptional changes in cord blood derived CD34+ cells at the single-cell level and integrating data with cell division history and morphological changes determined by time-lapse microscopy. We show, that major transcriptional changes leading to a multilineage-primed gene expression state occur very rapidly during the first cell cycle. One of the two stable lineage-primed patterns emerges gradually in each cell with variable timing. Some cells reach a stable morphology and molecular phenotype by the end of the first cell cycle and transmit it clonally. Others fluctuate between the two phenotypes over several cell cycles. Our analysis highlights the dynamic nature and variable timing of cell fate commitment in hematopoietic cells, links the gene expression pattern to cell morphology and identifies a new category of cells with fluctuating phenotypic characteristics, demonstrating the complexity of the fate decision process, away from a simple binary switch between two options as it is usually envisioned.

scholarly journals FGF signaling dynamics regulates epithelial patterning and morphogenesis

2020 ◽  
Author(s):  
Jakub Sumbal ◽  
Tereza Vranova ◽  
Zuzana Koledova
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Mammary Epithelium ◽  
Time Lapse ◽  
Branching Morphogenesis ◽  
Tissue Level ◽  
Epithelial Tissue ◽  
Growth Factor Signaling ◽  
Fgf Signaling ◽  
Signaling Dynamics

SummarySingle cell assays revealed that growth factor signaling dynamics is actively sensed by a cell and ultimately controls cell fate. However, the effects of growth factor signaling dynamics at the tissue level have been unknown. We used mammary epithelial organoids, time-lapse imaging, fibroblast growth factor 2 (FGF2) variants of different stabilities, mathematical modeling, and perturbation analysis to study the role of FGF2 signaling dynamics in epithelial morphogenesis. We found that fluctuant and sustained FGF signaling dynamics induced distinct morphological and functional states of mammary epithelium through differential employment of intracellular effectors ERK and AKT. ERK activity domains determined epithelial branch size, while AKT activity drove epithelial stratification. Furthermore, FGF signaling dynamics affected epithelial tissue mechanoresponsiveness to extracellular matrix, thereby impinging upon branch elongation. Our study provides new insights into regulation of epithelial patterning and branching morphogenesis by FGF signaling dynamics and into downstream signaling effectors that regulate cellular outcomes.

scholarly journals Polarization and cell-fate decision facilitated by the adaptor Ste50 in Saccharomyces cerevisiae

2021 ◽  
Author(s):  
Nusrat Sharmeen ◽  
Chris Law ◽  
Cunle Wu
Keyword(s):  
Cell Fate ◽  
Critical Role ◽  
Time Lapse ◽  
Yeast Cells ◽  
Cell Cortex ◽  
Dependent Manner ◽  
Pheromone Response ◽  
Concentration Dependent Manner ◽  
Directional Growth ◽  
Fate Decision

Polarization or directional growth is a major morphological change that occurs in yeast cells during pheromone response to mate with the opposite partner. In the pheromone signaling pathway, the adaptor Ste50 is required to bind MAP3K Ste11 for proper polarization; cells lacking Ste50 are impaired in polarization. Direct involvement of Ste50 in the polarization process has not been explored systematically. Here, we used single-cell fluorescent time-lapse microscopy to characterize Ste50 involvement in the establishment of cell polarity. We found early localization of Ste50 patches on the cell cortex that mark the point of shmoo initiation, these polarity sites move, and patches remain associated with the growing shmoo tip in a pheromone concentration-dependent manner until shmoo maturation. By quantitative analysis we show that polarization corelates with the rising levels of Ste50 enabling rapid individual cell responses to pheromone that corresponds to a critical level of Ste50 at the initial G1 phase. Suggesting Ste50 to be a pheromone responsive gene. We exploited the quantitative differences in the pattern of Ste50 expression to corelate with the cell-cell phenotypic heterogeneity showing Ste50 involvement in the cellular differentiation choices. Taken together, these findings present spatiotemporal localization of Ste50 during yeast polarization, suggesting that Ste50 is a component of the polarisome, and plays a critical role in regulating the polarized growth of shmoo during pheromone response.

scholarly journals The transcription factors STAT5A/B regulate GM-CSF–mediated granulopoiesis

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4721-4728 ◽  
Author(s):  
Akiko Kimura ◽  
Michael A. Rieger ◽  
James M. Simone ◽  
Weiping Chen ◽  
Mark C. Wickre ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Cell Tracking ◽  
Time Lapse ◽  
Vital Role ◽  
Immune Defense ◽  
Gm Csf ◽  
Emergency Situations ◽  
Macrophage Colony

Abstract Neutrophils play a vital role in the immune defense, which is evident by the severity of neutropenia causing life-threatening infections. Granulocyte macrophage-colony stimulating factor (GM-CSF) controls homeostatic and emergency development of granulocytes. However, little is known about the contribution of the downstream mediating transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A/B). To elucidate the function of this pathway, we generated mice with complete deletion of both Stat5a/b genes in hematopoietic cells. In homeostasis, peripheral neutrophils were markedly decreased in these animals. Moreover, during emergency situations, such as myelosuppression, Stat5a/b-mutant mice failed to produce enhanced levels of neutrophils and were unable to respond to GM-CSF. Both the GM-CSF–permitted survival of mature neutrophils and the generation of granulocytes from granulocyte-macrophage progenitors (GMPs) were markedly reduced in Stat5a/b mutants. GMPs showed impaired colony-formation ability with reduced number and size of colonies on GM-CSF stimulation. Moreover, continuous cell fate analyses by time-lapse microscopy and single cell tracking revealed that Stat5a/b-null GMPs showed both delayed cell-cycle progression and increased cell death. Finally, transcriptome analysis indicated that STAT5A/B directs GM-CSF signaling through the regulation of proliferation and survival genes.

scholarly journals Screening for gene expression fluctuations reveals latency-promoting agents of HIV

2021 ◽  
Vol 118 (11) ◽  
pp. e2012191118
Author(s):  
Yiyang Lu ◽  
Kathrin Bohn-Wippert ◽  
Patrick J. Pazerunas ◽  
Jennifer M. Moy ◽  
Harpal Singh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Thioredoxin Reductase ◽  
Time Lapse ◽  
Redox Balance ◽  
Single Cell Protein ◽  
Host Cells ◽  
Cell Protein ◽  
Latent Reservoir ◽  
Major Barrier

Upon treatment removal, spontaneous reactivation of latently infected T cells remains a major barrier toward curing HIV. Therapies that reactivate and clear the latent reservoir are only partially effective, while latency-promoting agents (LPAs) used to suppress reactivation and stabilize latency are understudied and lack diversity in their mechanisms of action. Here, we identify additional LPAs using a screen for gene-expression fluctuations (or “noise”) that drive cell-fate specification and control HIV reactivation from latency. Single-cell protein dynamics of a minimal HIV gene circuit were monitored with time-lapse fluorescence microscopy. We screened 1,806 drugs, out of which 279 modulate noise magnitude or half autocorrelation time. Next, we tested the strongest noise modulators in a Jurkat T cell latency model and discovered three LPAs that would be overlooked by quantifying their mean expression levels alone. The LPAs reduced reactivation of latency in both Jurkat and primary cell models when challenged by synergistic and potent combinations of HIV activators. The two strongest LPAs, NSC 401005 and NSC 400938, are structurally and functionally related to inhibitors of thioredoxin reductase, a protein involved in maintaining redox balance in host cells. Experiments with multiple functional analogs revealed two additional LPAs, PX12 and tiopronin, and suggest a potential LPA family, within which some are commercially available and Food and Drug Administration–approved. The LPAs presented here may provide new strategies to complement antiretroviral treatments. Screening for gene expression noise holds the potential for drug discovery in other diseases.

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