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Title: Cells respond to distinct nanoparticle properties with multiple strategies as revealed by single-cell RNA-Seq

Abstract

The impact of distinct nanoparticle (NP) properties on cellular response and ultimately human health is unclear. This gap is partially due to experimental difficulties in achieving uniform NP loads in the studied cells, creating heterogeneous populations with some cells “overloaded” while other cells are loaded with few or no NPs. Yet gene expression studies have been conducted in the population as a whole, identifying generic responses, while missing unique responses due to signal averaging across many cells, each carrying different loads. In this paper, we applied single-cell RNA-Seq to alveolar epithelial cells carrying defined loads of aminated or carboxylated quantum dots (QDs), showing higher or lower toxicity, respectively. Interestingly, cells carrying lower loads responded with multiple strategies, mostly with up-regulated processes, which were nonetheless coherent and unique to each QD type. In contrast, cells carrying higher loads responded more uniformly, with mostly down-regulated processes that were shared across QD types. Strategies unique to aminated QDs showed strong up-regulation of stress responses, coupled in some cases with regulation of cell cycle, protein synthesis, and organelle activities. In contrast, strategies unique to carboxylated QDs showed up-regulation of DNA repair and RNA activities and decreased regulation of cell division, coupled in some casesmore » with up-regulation of stress responses and ATP-related functions. Finally, together, our studies suggest scenarios where higher NP loads lock cells into uniform responses, mostly shutdown of cellular processes, whereas lower loads allow for unique responses to each NP type that are more diversified proactive defenses or repairs of the NP insults.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [2];  [1]
  1. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Earth and Biological Sciences Directorate
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). National Security Directorate
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1330718
Grant/Contract Number:  
AC05-76RL01830; 1RC2ES018786-01
Resource Type:
Accepted Manuscript
Journal Name:
ACS Nano
Additional Journal Information:
Journal Volume: 10; Journal Issue: 11; Journal ID: ISSN 1936-0851
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; single cell sorting; transcriptional response; hierarchical clustering; functional enrichment; differential gene expression

Citation Formats

Mitchell, Hugh D., Markillie, Lye Meng, Chrisler, William B., Gaffrey, Matthew J., Hu, Dehong, Szymanski, Craig J., Xie, Yumei, Melby, Eric S., Dohnalkova, Alice, Taylor, Ronald C., Grate, Eva K., Cooley, Scott K., McDermott, Jason E., Heredia-Langner, Alejandro, and Orr, Galya. Cells respond to distinct nanoparticle properties with multiple strategies as revealed by single-cell RNA-Seq. United States: N. p., 2016. Web. doi:10.1021/acsnano.6b05452.
Mitchell, Hugh D., Markillie, Lye Meng, Chrisler, William B., Gaffrey, Matthew J., Hu, Dehong, Szymanski, Craig J., Xie, Yumei, Melby, Eric S., Dohnalkova, Alice, Taylor, Ronald C., Grate, Eva K., Cooley, Scott K., McDermott, Jason E., Heredia-Langner, Alejandro, & Orr, Galya. Cells respond to distinct nanoparticle properties with multiple strategies as revealed by single-cell RNA-Seq. United States. doi:10.1021/acsnano.6b05452.
Mitchell, Hugh D., Markillie, Lye Meng, Chrisler, William B., Gaffrey, Matthew J., Hu, Dehong, Szymanski, Craig J., Xie, Yumei, Melby, Eric S., Dohnalkova, Alice, Taylor, Ronald C., Grate, Eva K., Cooley, Scott K., McDermott, Jason E., Heredia-Langner, Alejandro, and Orr, Galya. Thu . "Cells respond to distinct nanoparticle properties with multiple strategies as revealed by single-cell RNA-Seq". United States. doi:10.1021/acsnano.6b05452. https://www.osti.gov/servlets/purl/1330718.
@article{osti_1330718,
title = {Cells respond to distinct nanoparticle properties with multiple strategies as revealed by single-cell RNA-Seq},
author = {Mitchell, Hugh D. and Markillie, Lye Meng and Chrisler, William B. and Gaffrey, Matthew J. and Hu, Dehong and Szymanski, Craig J. and Xie, Yumei and Melby, Eric S. and Dohnalkova, Alice and Taylor, Ronald C. and Grate, Eva K. and Cooley, Scott K. and McDermott, Jason E. and Heredia-Langner, Alejandro and Orr, Galya},
abstractNote = {The impact of distinct nanoparticle (NP) properties on cellular response and ultimately human health is unclear. This gap is partially due to experimental difficulties in achieving uniform NP loads in the studied cells, creating heterogeneous populations with some cells “overloaded” while other cells are loaded with few or no NPs. Yet gene expression studies have been conducted in the population as a whole, identifying generic responses, while missing unique responses due to signal averaging across many cells, each carrying different loads. In this paper, we applied single-cell RNA-Seq to alveolar epithelial cells carrying defined loads of aminated or carboxylated quantum dots (QDs), showing higher or lower toxicity, respectively. Interestingly, cells carrying lower loads responded with multiple strategies, mostly with up-regulated processes, which were nonetheless coherent and unique to each QD type. In contrast, cells carrying higher loads responded more uniformly, with mostly down-regulated processes that were shared across QD types. Strategies unique to aminated QDs showed strong up-regulation of stress responses, coupled in some cases with regulation of cell cycle, protein synthesis, and organelle activities. In contrast, strategies unique to carboxylated QDs showed up-regulation of DNA repair and RNA activities and decreased regulation of cell division, coupled in some cases with up-regulation of stress responses and ATP-related functions. Finally, together, our studies suggest scenarios where higher NP loads lock cells into uniform responses, mostly shutdown of cellular processes, whereas lower loads allow for unique responses to each NP type that are more diversified proactive defenses or repairs of the NP insults.},
doi = {10.1021/acsnano.6b05452},
journal = {ACS Nano},
number = 11,
volume = 10,
place = {United States},
year = {2016},
month = {10}
}

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