scholarly journals Heterogeneity of Sonic Hedgehog Response Dynamics and Fate Specification in Single Neural Progenitors

2018 ◽  
Author(s):  
Fengzhu Xiong ◽  
Andrea R. Tentner ◽  
Tom W. Hiscock ◽  
Peng Huang ◽  
Sean G. Megason
Keyword(s):  
Cell Fate ◽  
Sonic Hedgehog ◽  
Cellular Response ◽  
Single Cells ◽  
Neural Progenitors ◽  
Significant Heterogeneity ◽  
Response Dynamics ◽  
Output Analysis ◽  
Response Level ◽  
Fate Specification

SUMMARYDuring neural tube patterning, a gradient of Sonic hedgehog (Shh) signaling specifies ventral progenitor fates. The cellular response to Shh is processed through a genetic regulatory network (GRN) to code distinct fate decisions. This process integrates Shh response level, duration and other inputs and is affected by noise in signaling and cell position. How reliably a single cell’s Shh response profile predicts its fate choice is unclear. Here we use live imaging to track neural progenitors that carry both Shh and fate reporters in zebrafish embryos. We found that there is significant heterogeneity between Shh response and fate choice in single cells. We quantitatively modeled reporter intensities to obtain single cell response levels over time and systematically determined their correlation with multiple models of cell fate specification. Our input-output analysis shows that while no single metric perfectly predicts fate choices, the maximal Shh response level correlates best overall with progenitor fate choices across the anterior-posterior axis.

Use of Flexible Materials with a Novel Pressure Driven Equibiaxial Cell Stretching Device for Mechanical Stimulation of Single Mammalian Cells

2003 ◽  
Vol 773 ◽  
Author(s):  
James D. Kubicek ◽  
Stephanie Brelsford ◽  
Philip R. LeDuc
Keyword(s):  
Cell Fate ◽  
Mechanical Stimulation ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Single Cells ◽  
Complex Nature ◽  
Cellular Behavior ◽  
Cell Stretching ◽  
Stimulation Of ◽  
Pressure Driven

AbstractMechanical stimulation of single cells has been shown to affect cellular behavior from the molecular scale to ultimate cell fate including apoptosis and proliferation. In this, the ability to control the spatiotemporal application of force on cells through their extracellular matrix connections is critical to understand the cellular response of mechanotransduction. Here, we develop and utilize a novel pressure-driven equibiaxial cell stretching device (PECS) combined with an elastomeric material to control specifically the mechanical stimulation on single cells. Cells were cultured on silicone membranes coated with molecular matrices and then a uniform pressure was introduced to the opposite surface of the membrane to stretch single cells equibiaxially. This allowed us to apply mechanical deformation to investigate the complex nature of cell shape and structure. These results will enhance our knowledge of cellular and molecular function as well as provide insights into fields including biomechanics, tissue engineering, and drug discovery.

scholarly journals Cell-to-cell variability in inducible Caspase9-mediated cell death

2021 ◽  
Author(s):  
Yuan Yuan ◽  
Huixia Ren ◽  
Yanjun Li ◽  
Shanshan Qin ◽  
Xiaojing Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cell Fate ◽  
Single Cells ◽  
Suicide Gene ◽  
Significant Heterogeneity ◽  
Cell Therapies ◽  
Protein Levels ◽  
Multiple Round ◽  
Cell To Cell Variability

iCasp9 suicide gene has been widely used as a promising killing strategy in various cell therapies. However, different cells show significant heterogeneity in response to apoptosis inducer, posing challenges in clinical applications of killing strategy. The cause of the heterogeneity remains elusive so far. Here, by simultaneously monitoring the dynamics of iCasp9 dimerization, Caspase3 activation and cell fate in single cells, we found that the heterogeneity was mainly due to cell-to-cell variability in initial iCasp9 expression and XIAP/Caspase3 ratio. Moreover, multiple-round drugging cannot increase the killing efficiency. Instead, it will place selective pressure on protein levels, especially on the level of initial iCasp9, leading to drug resistance. We further show this resistance can be largely eliminated by combinatorial drugging with XIAP inhibitor at the end, but not at the beginning, of the multiple-round treatments. Our results unveil the source of cell fate heterogeneity and drug resistance in iCasp9-mediated cell death, which may enlighten better therapeutic strategies for optimized killing.

scholarly journals Multiplexed biochemical imaging reveals caspase activation patterns underlying single cell fate

2018 ◽  
Author(s):  
Maximilian W. Fries ◽  
Kalina T. Haas ◽  
Suzan Ber ◽  
John Saganty ◽  
Emma K. Richardson ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Cell ◽  
Cell Fate ◽  
Genetic Heterogeneity ◽  
Cellular Response ◽  
Single Cells ◽  
Caspase Activation ◽  
Cell Fate Decisions ◽  
Network Activation ◽  
Biochemical Imaging

The biochemical activities underlying cell-fate decisions vary profoundly even in genetically identical cells. But such non-genetic heterogeneity remains refractory to current imaging methods, because their capacity to monitor multiple biochemical activities in single living cells over time remains limited1. Here, we deploy a family of newly designed GFP-like sensors (NyxBits) with fast photon-counting electronics and bespoke analytics (NyxSense) in multiplexed biochemical imaging, to define a network determining the fate of single cells exposed to the DNA-damaging drug cisplatin. By simultaneously imaging a tri-nodal network comprising the cell-death proteases Caspase-2, -3 and -92, we reveal unrecognized single-cell heterogeneities in the dynamics and amplitude of caspase activation that signify survival versus cell death via necrosis or apoptosis. Non-genetic heterogeneity in the pattern of caspase activation recapitulates traits of therapy resistance previously ascribed solely to genetic causes3,4. Chemical inhibitors that alter these patterns can modulate in a predictable manner the phenotypic landscape of the cellular response to cisplatin. Thus, multiplexed biochemical imaging reveals cellular populations and biochemical states, invisible to other methods, underlying therapeutic responses to an anticancer drug. Our work develops widely applicable tools to monitor the dynamic activation of biochemical networks at single-cell resolution. It highlights the necessity to resolve patterns of network activation in single cells, rather than the average state of individual nodes, to define, and potentially control, mechanisms underlying cellular decisions in health and disease.

scholarly journals Cell-to-cell variability in inducible Caspase9-mediated cell death

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yuan Yuan ◽  
Huixia Ren ◽  
Yanjun Li ◽  
Shanshan Qin ◽  
Xiaojing Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cell Fate ◽  
Single Cells ◽  
Suicide Gene ◽  
Significant Heterogeneity ◽  
Cell Therapies ◽  
Protein Levels ◽  
Multiple Round ◽  
Cell To Cell Variability

AbstractiCasp9 suicide gene has been widely used as a promising killing strategy in various cell therapies. However, different cells show significant heterogeneity in response to apoptosis inducer, posing challenges in clinical applications of killing strategy. The cause of the heterogeneity remains elusive so far. Here, by simultaneously monitoring the dynamics of iCasp9 dimerization, Caspase3 activation, and cell fate in single cells, we found that the heterogeneity was mainly due to cell-to-cell variability in initial iCasp9 expression and XIAP/Caspase3 ratio. Moreover, multiple-round drugging cannot increase the killing efficiency. Instead, it will place selective pressure on protein levels, especially on the level of initial iCasp9, leading to drug resistance. We further show this resistance can be largely eliminated by combinatorial drugging with XIAP inhibitor at the end, but not at the beginning, of the multiple-round treatments. Our results unveil the source of cell fate heterogeneity and drug resistance in iCasp9-mediated cell death, which may enlighten better therapeutic strategies for optimized killing.

scholarly journals Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid

PLoS Genetics ◽  
2017 ◽  
Vol 13 (7) ◽  
pp. e1006914 ◽  
Author(s):  
Maha El Shahawy ◽  
Claes-Göran Reibring ◽  
Cynthia L. Neben ◽  
Kristina Hallberg ◽  
Pauline Marangoni ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Sonic Hedgehog ◽  
Cell Fate Specification ◽  
Lingual Epithelium ◽  
Fate Specification

scholarly journals Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xudong Zhu ◽  
Zhiyang Chen ◽  
Weiyan Shen ◽  
Gang Huang ◽  
John M. Sedivy ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Response ◽  
State Of The Art ◽  
Cell Senescence ◽  
Therapeutic Interventions ◽  
Cell Fate Decision ◽  
The Past ◽  
Fate Decision ◽  
The Individual ◽  
Remarkable Progress

AbstractRemarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.

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