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Special Issue "Single Cell Analysis in Biotechnology and Systems Biology"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2015).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Fan-Gang Tseng
E-Mail Website
Guest Editor
Department of Engineering and System Science, Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan
Interests: MEMS/NEMS; microfluidics; 3D tissue culture; electrochemical sensors; nanotechnology in biomedical applications
Special Issues, Collections and Topics in MDPI journals
Dr. Tuhin Subhra Santra
E-Mail Website
Guest Editor

Special Issue Information

Dear Colleagues,

Cells play significant roles in our day to day life. However, the interactions of cells, the cellular responses of organelles to molecules, and their intracellular behaviour, are still not fully understood. To better understand the physiological interactions among molecules, organelles, and cells, the ensemble measurement of (on average, millions of) cells cannot provide detailed information. However, for example, research concerning the differentiation behaviors of stem cells or the metastatic processes of tumour initiation requires detailed information. Understanding genomic sequence information at a single cell level can promote an understanding of how individual parts of a cell are integrated in time and space to form dynamic cellular processes. The relationship between cellular heterogeneity and signaling pathway regulation may result in an understanding of disease states that can potentially drive therapeutic interventions. Thus single cell analysis (SCA) has been emerging as a powerful method of investigating exciting new insights into genomics, metabolomics, fluxomics, proteomics, and systems biology. This Special Issue invites the latest research articles and reviews concerning single cell analysis in biotechnology, systems biology, and their different potential applications in bioprocess engineering.

Prof. Dr. Fan-Gang Tseng
Dr. Tuhin Subhra Santra
Guest Editors

Manuscript Submission Information

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Keywords

  • single cell heterogeneity
  • single cell in system biology
  • cellular complexity
  • micro/nano fluidic single cell analysis
  • single cell cultivation
  • single cell perturbation
  • single cell cytometry
  • single cell manipulation, separation, detection
  • single cell electroporation, microinjection, optoporation, thermoporation and magnetoporation
  • single cell genomics, proteomics, metabolomics and fluxomics
  • single cell diagnostic and imaging

Related Special Issue

Published Papers (10 papers)

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Research

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Article
Numerical Analysis of Hydrodynamic Flow in Microfluidic Biochip for Single-Cell Trapping Application
Int. J. Mol. Sci. 2015, 16(11), 26770-26785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161125987 - 09 Nov 2015
Cited by 9 | Viewed by 3650
Abstract
Single-cell analysis has become the interest of a wide range of biological and biomedical engineering research. It could provide precise information on individual cells, leading to important knowledge regarding human diseases. To perform single-cell analysis, it is crucial to isolate the individual cells [...] Read more.
Single-cell analysis has become the interest of a wide range of biological and biomedical engineering research. It could provide precise information on individual cells, leading to important knowledge regarding human diseases. To perform single-cell analysis, it is crucial to isolate the individual cells before further manipulation is carried out. Recently, microfluidic biochips have been widely used for cell trapping and single cell analysis, such as mechanical and electrical detection. This work focuses on developing a finite element simulation model of single-cell trapping system for any types of cells or particles based on the hydrodynamic flow resistance (Rh) manipulations in the main channel and trap channel to achieve successful trapping. Analysis is carried out using finite element ABAQUS-FEA™ software. A guideline to design and optimize single-cell trapping model is proposed and the example of a thorough optimization analysis is carried out using a yeast cell model. The results show the finite element model is able to trap a single cell inside the fluidic environment. Fluid’s velocity profile and streamline plots for successful and unsuccessful single yeast cell trapping are presented according to the hydrodynamic concept. The single-cell trapping model can be a significant important guideline in designing a new chip for biomedical applications. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Article
Evidence for P-Glycoprotein Involvement in Cell Volume Regulation Using Coulter Sizing in Flow Cytometry
Int. J. Mol. Sci. 2015, 16(7), 14318-14337; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160714318 - 24 Jun 2015
Cited by 2 | Viewed by 3355
Abstract
The regulation of cell volume is an essential function that is coupled to a variety of physiological processes such as receptor recycling, excitability and contraction, cell proliferation, migration, and programmed cell death. Under stress, cells undergo emergency swelling and respond to such a [...] Read more.
The regulation of cell volume is an essential function that is coupled to a variety of physiological processes such as receptor recycling, excitability and contraction, cell proliferation, migration, and programmed cell death. Under stress, cells undergo emergency swelling and respond to such a phenomenon with a regulatory volume decrease (RVD) where they release cellular ions, and other osmolytes as well as a concomitant loss of water. The link between P-glycoprotein, a transmembrane transporter, and cell volume regulation is controversial, and changes in cells volume are measured using microscopy or electrophysiology. For instance, by using the patch-clamp method, our team demonstrated that chloride currents activated in the RVD were more intense and rapid in a breast cancer cell line overexpressing the P-glycoprotein (P-gp). The Cell Lab Quanta SC is a flow cytometry system that simultaneously measures electronic volume, side scatter and three fluorescent colors; altogether this provides unsurpassed population resolution and accurate cell counting. Therefore, here we propose a novel method to follow cellular volume. By using the Coulter-type channel of the cytometer Cell Lab Quanta SC MPL (multi-platform loading), we demonstrated a role for the P-gp during different osmotic treatments, but also a differential activity of the P-gp through the cell cycle. Altogether, our data strongly suggests a role of P-gp in cell volume regulation. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review

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Review
Single-Cell Isolation and Gene Analysis: Pitfalls and Possibilities
Int. J. Mol. Sci. 2015, 16(11), 26832-26849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161125996 - 10 Nov 2015
Cited by 20 | Viewed by 5242
Abstract
During the last two decades single-cell analysis (SCA) has revealed extensive phenotypic differences within homogenous cell populations. These phenotypic differences are reflected in the stochastic nature of gene regulation, which is often masked by qualitatively and quantitatively averaging in whole tissue analyses. The [...] Read more.
During the last two decades single-cell analysis (SCA) has revealed extensive phenotypic differences within homogenous cell populations. These phenotypic differences are reflected in the stochastic nature of gene regulation, which is often masked by qualitatively and quantitatively averaging in whole tissue analyses. The ability to isolate transcripts and investigate how genes are regulated at the single cell level requires highly sensitive and refined methods. This paper reviews different strategies currently used for SCA, including harvesting, reverse transcription, and amplification of the RNA, followed by methods for transcript quantification. The review provides the historical background to SCA, discusses limitations, and current and future possibilities in this exciting field of research. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
Digital Microfluidics for Manipulation and Analysis of a Single Cell
Int. J. Mol. Sci. 2015, 16(9), 22319-22332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160922319 - 15 Sep 2015
Cited by 39 | Viewed by 4535
Abstract
The basic structural and functional unit of a living organism is a single cell. To understand the variability and to improve the biomedical requirement of a single cell, its analysis has become a key technique in biological and biomedical research. With a physical [...] Read more.
The basic structural and functional unit of a living organism is a single cell. To understand the variability and to improve the biomedical requirement of a single cell, its analysis has become a key technique in biological and biomedical research. With a physical boundary of microchannels and microstructures, single cells are efficiently captured and analyzed, whereas electric forces sort and position single cells. Various microfluidic techniques have been exploited to manipulate single cells through hydrodynamic and electric forces. Digital microfluidics (DMF), the manipulation of individual droplets holding minute reagents and cells of interest by electric forces, has received more attention recently. Because of ease of fabrication, compactness and prospective automation, DMF has become a powerful approach for biological application. We review recent developments of various microfluidic chips for analysis of a single cell and for efficient genetic screening. In addition, perspectives to develop analysis of single cells based on DMF and emerging functionality with high throughput are discussed. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
Detecting Antigen-Specific T Cell Responses: From Bulk Populations to Single Cells
Int. J. Mol. Sci. 2015, 16(8), 18878-18893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160818878 - 12 Aug 2015
Cited by 15 | Viewed by 4374
Abstract
A new generation of sensitive T cell-based assays facilitates the direct quantitation and characterization of antigen-specific T cell responses. Single-cell analyses have focused on measuring the quality and breadth of a response. Accumulating data from these studies demonstrate that there is considerable, previously-unrecognized, [...] Read more.
A new generation of sensitive T cell-based assays facilitates the direct quantitation and characterization of antigen-specific T cell responses. Single-cell analyses have focused on measuring the quality and breadth of a response. Accumulating data from these studies demonstrate that there is considerable, previously-unrecognized, heterogeneity. Standard assays, such as the ICS, are often insufficient for characterization of rare subsets of cells. Enhanced flow cytometry with imaging capabilities enables the determination of cell morphology, as well as the spatial localization of the protein molecules within a single cell. Advances in both microfluidics and digital PCR have improved the efficiency of single-cell sorting and allowed multiplexed gene detection at the single-cell level. Delving further into the transcriptome of single-cells using RNA-seq is likely to reveal the fine-specificity of cellular events such as alternative splicing (i.e., splice variants) and allele-specific expression, and will also define the roles of new genes. Finally, detailed analysis of clonally related antigen-specific T cells using single-cell TCR RNA-seq will provide information on pathways of differentiation of memory T cells. With these state of the art technologies the transcriptomics and genomics of Ag-specific T cells can be more definitively elucidated. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
A Review of Cell Adhesion Studies for Biomedical and Biological Applications
Int. J. Mol. Sci. 2015, 16(8), 18149-18184; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160818149 - 05 Aug 2015
Cited by 375 | Viewed by 9545
Abstract
Cell adhesion is essential in cell communication and regulation, and is of fundamental importance in the development and maintenance of tissues. The mechanical interactions between a cell and its extracellular matrix (ECM) can influence and control cell behavior and function. The essential function [...] Read more.
Cell adhesion is essential in cell communication and regulation, and is of fundamental importance in the development and maintenance of tissues. The mechanical interactions between a cell and its extracellular matrix (ECM) can influence and control cell behavior and function. The essential function of cell adhesion has created tremendous interests in developing methods for measuring and studying cell adhesion properties. The study of cell adhesion could be categorized into cell adhesion attachment and detachment events. The study of cell adhesion has been widely explored via both events for many important purposes in cellular biology, biomedical, and engineering fields. Cell adhesion attachment and detachment events could be further grouped into the cell population and single cell approach. Various techniques to measure cell adhesion have been applied to many fields of study in order to gain understanding of cell signaling pathways, biomaterial studies for implantable sensors, artificial bone and tooth replacement, the development of tissue-on-a-chip and organ-on-a-chip in tissue engineering, the effects of biochemical treatments and environmental stimuli to the cell adhesion, the potential of drug treatments, cancer metastasis study, and the determination of the adhesion properties of normal and cancerous cells. This review discussed the overview of the available methods to study cell adhesion through attachment and detachment events. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
Technologies for Single-Cell Isolation
Int. J. Mol. Sci. 2015, 16(8), 16897-16919; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160816897 - 24 Jul 2015
Cited by 186 | Viewed by 11642
Abstract
The handling of single cells is of great importance in applications such as cell line development or single-cell analysis, e.g., for cancer research or for emerging diagnostic methods. This review provides an overview of technologies that are currently used or in development to [...] Read more.
The handling of single cells is of great importance in applications such as cell line development or single-cell analysis, e.g., for cancer research or for emerging diagnostic methods. This review provides an overview of technologies that are currently used or in development to isolate single cells for subsequent single-cell analysis. Data from a dedicated online market survey conducted to identify the most relevant technologies, presented here for the first time, shows that FACS (fluorescence activated cell sorting) respectively Flow cytometry (33% usage), laser microdissection (17%), manual cell picking (17%), random seeding/dilution (15%), and microfluidics/lab-on-a-chip devices (12%) are currently the most frequently used technologies. These most prominent technologies are described in detail and key performance factors are discussed. The survey data indicates a further increasing interest in single-cell isolation tools for the coming years. Additionally, a worldwide patent search was performed to screen for emerging technologies that might become relevant in the future. In total 179 patents were found, out of which 25 were evaluated by screening the title and abstract to be relevant to the field. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
Get to Understand More from Single-Cells: Current Studies of Microfluidic-Based Techniques for Single-Cell Analysis
Int. J. Mol. Sci. 2015, 16(8), 16763-16777; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160816763 - 23 Jul 2015
Cited by 23 | Viewed by 4516
Abstract
This review describes the microfluidic techniques developed for the analysis of a single cell. The characteristics of microfluidic (e.g., little sample amount required, high-throughput performance) make this tool suitable to answer and to solve biological questions of interest about a single cell. This [...] Read more.
This review describes the microfluidic techniques developed for the analysis of a single cell. The characteristics of microfluidic (e.g., little sample amount required, high-throughput performance) make this tool suitable to answer and to solve biological questions of interest about a single cell. This review aims to introduce microfluidic related techniques for the isolation, trapping and manipulation of a single cell. The major approaches for detection in single-cell analysis are introduced; the applications of single-cell analysis are then summarized. The review concludes with discussions of the future directions and opportunities of microfluidic systems applied in analysis of a single cell. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
Single Cell Electrical Characterization Techniques
Int. J. Mol. Sci. 2015, 16(6), 12686-12712; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160612686 - 04 Jun 2015
Cited by 41 | Viewed by 4441
Abstract
Electrical properties of living cells have been proven to play significant roles in understanding of various biological activities including disease progression both at the cellular and molecular levels. Since two decades ago, many researchers have developed tools to analyze the cell’s electrical states [...] Read more.
Electrical properties of living cells have been proven to play significant roles in understanding of various biological activities including disease progression both at the cellular and molecular levels. Since two decades ago, many researchers have developed tools to analyze the cell’s electrical states especially in single cell analysis (SCA). In depth analysis and more fully described activities of cell differentiation and cancer can only be accomplished with single cell analysis. This growing interest was supported by the emergence of various microfluidic techniques to fulfill high precisions screening, reduced equipment cost and low analysis time for characterization of the single cell’s electrical properties, as compared to classical bulky technique. This paper presents a historical review of single cell electrical properties analysis development from classical techniques to recent advances in microfluidic techniques. Technical details of the different microfluidic techniques are highlighted, and the advantages and limitations of various microfluidic devices are discussed. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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Review
Microfluidic Impedance Flow Cytometry Enabling High-Throughput Single-Cell Electrical Property Characterization
Int. J. Mol. Sci. 2015, 16(5), 9804-9830; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16059804 - 29 Apr 2015
Cited by 94 | Viewed by 5851
Abstract
This article reviews recent developments in microfluidic impedance flow cytometry for high-throughput electrical property characterization of single cells. Four major perspectives of microfluidic impedance flow cytometry for single-cell characterization are included in this review: (1) early developments of microfluidic impedance flow cytometry for [...] Read more.
This article reviews recent developments in microfluidic impedance flow cytometry for high-throughput electrical property characterization of single cells. Four major perspectives of microfluidic impedance flow cytometry for single-cell characterization are included in this review: (1) early developments of microfluidic impedance flow cytometry for single-cell electrical property characterization; (2) microfluidic impedance flow cytometry with enhanced sensitivity; (3) microfluidic impedance and optical flow cytometry for single-cell analysis and (4) integrated point of care system based on microfluidic impedance flow cytometry. We examine the advantages and limitations of each technique and discuss future research opportunities from the perspectives of both technical innovation and clinical applications. Full article
(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)
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