Skip to main content
SpringerLink
Log in

Mass Spectrometry for Single-Cell Analysis

  • Living reference work entry
  • First Online:
Handbook of Single Cell Technologies

  • 164 Accesses

Abstract

Cells are the basic structural and functional units in biology that plays important roles in living organisms. It can be affected by several factors that influence their proliferation, differentiation, and metabolic activities and consequently causing the wide heterogeneity among each cell within the same individual. It has been noted that the chemical composition and concentration found in two homogeneous cells are also different. Therefore, accurate cell morphology and composition can be obtained by studying at the single-cell level in a particular microenvironment. Nucleic acids, proteins, trace elements, and small molecule metabolites are the important chemicals present in cells and play key roles in cellular processes. Various analytic techniques such as flow cytometry, fluorescence microscopy, Raman microscopy, and mass spectrometry are used for single-cell analysis. Each technique has own advantages and disadvantages. Among them, mass spectrometry (MS) technique has received a considerable amount of attention owing to its high susceptibility and superior potential for the revealing of various molecules without any chemical agents. In addition, low sample consumption with high detection potential makes the MS technique suitable for single-cell analysis on the cellular level. Here, we concisely demonstrated the different kinds of MS techniques with their merits and demerits that are widely explored for single-cell analysis at cellular and subcellular levels.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  • Abdelhamid H, Wu H (2015) Synthesis of a highly dispersive sinapinic acid@graphene oxide (SA@GO) and its applications as a novel surface assisted laser desorption/ionization mass spectrometry for proteomics and pathogenic bacteria biosensing. Analyst 140(5):1555–1565

    Google Scholar 

  • Abed S, Zou X, Ali A, Jin Q, Wang X (2017) Profiling of triacylglycerol composition in arachidonic acid single cell oil from Mortierella alpina by using ultra-performance liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry. J Food Compos Anal 62:245–253

    Google Scholar 

  • Ali A, Abouleila Y, Shimizu Y, Hiyama E, Emara S, Mashaghi A, Hankemeier T (2019) Single-cell metabolomics by mass spectrometry: advances, challenges, and future applications. TrAC Trend Anal Chem. https://doi.org/10.1016/j.trac.2019.02.033

  • Angerer T, Magnusson Y, Landberg G, Fletcher J (2016) Lipid heterogeneity resulting from fatty acid processing in the human breast cancer microenvironment identified by GCIB-ToF-SIMS imaging. Anal Chem 88(23):11946–11954

    Google Scholar 

  • Aoyagi S, Shimanouchi T, Kawashima T, Iwai H (2015) ToF-SIMS observation for evaluating the interaction between amyloid β and lipid membranes. Anal Bioanal Chem 407(10):2859–2863

    Google Scholar 

  • Bateman N, Conrads T (2018) Recent advances and opportunities in proteomic analyses of tumour heterogeneity. J Pathol 244(5):628–637

    Google Scholar 

  • Bendall S, Nolan G, Roederer M, Chattopadhyay P (2012) A deep profiler’s guide to cytometry. Trends Immunol 33(7):323–332

    Google Scholar 

  • Bishop D, Grossgarten M, Dietrich D, Vennemann A, Cole N, Sperling M, Wiemann M, Doble P, Karst U (2018) Correction: quantitative imaging of translocated silver following nanoparticle exposure by laser ablation-inductively coupled plasma-mass spectrometry. Anal Methods 10(8):926–926

    Google Scholar 

  • Bonta M, Lohninger H, Marchetti-Deschmann M, Limbeck A (2014) Application of gold thin-films for internal standardization in LA-ICP-MS imaging experiments. Analyst 139(6):1521

    Google Scholar 

  • Calavia R, Annanouch F, Correig X, Yanes O (2012) Nanostructure initiator mass spectrometry for tissue imaging in metabolomics: future prospects and perspectives. J Proteomics 75(16): 5061–5068

    Google Scholar 

  • Cao Z, Wu S (2017) Current research development of single cell genome in urological tumor. Int J Biochem Cell Biol 90:167–171

    Google Scholar 

  • Cerchiaro G, Manieri T, Bertuchi F (2013) Analytical methods for copper, zinc and iron quantification in mammalian cells. Metallomics 5(10):1336

    Google Scholar 

  • Cheng Y, Chen K, Wang J, Hsu W, Chien C, Chen W, Tsao C (2012) Rapid analysis of abused drugs using nanostructured silicon surface assisted laser desorption/ionization mass spectrometry. Analyst 137(3):654–661

    Google Scholar 

  • Coskun A, Eser U, Islam S (2016) Cellular identity at the single-cell level. Mol Biosyst 12(10):2965–2979

    Google Scholar 

  • Crotti S, Seraglia R, Traldi P (2011) Some thoughts on electrospray ionization mechanisms. Eur J Mass Spectrom 17(2):85–99

    Google Scholar 

  • Duncan K, Fyrestam J, Lanekoff I (2019) Advances in mass spectrometry based single-cell metabolomics. Analyst 144(3):782–793

    Google Scholar 

  • Elci S, Yan B, Kim S, Saha K, Jiang Y, Klemmer G, Moyano D, Tonga G, Rotello V, Vachet R (2016) Quantitative imaging of 2 nm monolayer-protected gold nanoparticle distributions in tissues using laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS). Analyst 141(8):2418–2425

    Google Scholar 

  • Etxebarria J, Calvo J, Reichardt N (2014) Nanostructured weathering steel for matrix-free laser desorption ionisation mass spectrometry and imaging of metabolites, drugs and complex glycans. Analyst 139(11):2873–2883

    Google Scholar 

  • Evans C, Ling J (2017) Visualizing translational errors: one cell at a time. Curr Genet 64(3): 551–554

    Google Scholar 

  • Gao J, Louie K, Steinke P, Bowen B, Raad M, Zuckermann R, Siuzdak G, Northen T (2017) Morphology-driven control of metabolite selectivity using nanostructure-initiator mass spectrometry. Anal Chem 89(12):6521–6526

    Google Scholar 

  • Gessel M, Norris J, Caprioli R (2014) MALDI imaging mass spectrometry: spatial molecular analysis to enable a new age of discovery. J Proteomics 107:71–82

    Google Scholar 

  • Gong X, Zhao Y, Cai S, Fu S, Yang C, Zhang S, Zhang X (2014) Single cell analysis with probe ESI-Mass spectrometry: detection of metabolites at cellular and subcellular levels. Anal Chem 86(8):3809–3816

    Google Scholar 

  • Grate J, Gonzalez J, O’Hara M, Kellogg C, Morrison S, Koppenaal D, Chan G, Mao X, Zorba V, Russo R (2017) Solid matrix transformation and tracer addition using molten ammonium bifluoride salt as a sample preparation method for laser ablation inductively coupled plasma mass spectrometry. Analyst 142(18):3333–3340

    Google Scholar 

  • Greving M, Patti G, Siuzdak G (2011) Nanostructure-initiator mass spectrometry metabolite analysis and imaging. Anal Chem 83(1):2–7

    Google Scholar 

  • Gries U, Schraknepper H, Skaja K, Gunkel F, Hoffmann-Eifert S, Waser R, De Souza R (2018) A SIMS study of cation and anion diffusion in tantalum oxide. Phys Chem Chem Phys 20(2):989–996

    Google Scholar 

  • Guillaume-Gentil O, Rey T, Kiefer P, Ibáñez A, Steinhoff R, Brönnimann R, Dorwling-Carter L, Zambelli T, Zenobi R, Vorholt J (2017) Single-cell mass spectrometry of metabolites extracted from live cells by fluidic force microscopy. Anal Chem 89(9):5017–5023

    Google Scholar 

  • Gutierrez G, Gromada J, Sussel L (2017) Heterogeneity of the pancreatic beta cell. Front Genet 8:1–9

    Google Scholar 

  • Haraguchi H (2017) Metallomics: the history over the last decade and a future outlook. Metallomics 9(8):1001–1013

    Google Scholar 

  • Herrmann A, Techritz S, Jakubowski N, Haase A, Luch A, Panne U, Mueller L (2017) A simple metal staining procedure for identification and visualization of single cells by LA-ICP-MS. Analyst 142(10):1703–1710

    Google Scholar 

  • Hua X, Li H, Long Y (2017) Investigation of silver nanoparticle induced lipids changes on a single cell surface by time-of-flight secondary ion mass spectrometry. Anal Chem 90(2):1072–1076

    Google Scholar 

  • Le Pogam P, Schinkovitz A, Legouin B, Le Lamer A, Boustie J, Richomme P (2015) Matrix-free UV-laser desorption ionization mass spectrometry as a versatile approach for accelerating dereplication studies on lichens. Anal Chem 87(20):10421–10428

    Google Scholar 

  • Li F, Armstrong D, Houk R (2005) Behavior of bacteria in the inductively coupled plasma: atomization and production of atomic ions for mass spectrometry. Anal Chem 77(5):1407–1413

    Google Scholar 

  • Li X, Zhao S, Liu Y (2016) Real-time chiral metabolic monitoring of single cell using microchip electrophoresis coupled with electrospray ionization mass spectrometry. ChemistrySelect 1(17):5554–5560

    Google Scholar 

  • Lin Y, Trouillon R, Safina G, Ewing A (2011) Chemical analysis of single cells. Anal Chem 83(12):4369–4392

    Google Scholar 

  • Liu J, Aerts J, Rubakhin S, Zhang X, Sweedler J (2014) Analysis of endogenous nucleotides by single cell capillary electrophoresis-mass spectrometry. Analyst 139(22):5835–5842

    Google Scholar 

  • Lombard-Banek C, Reddy S, Moody S, Nemes P (2016) Label-free quantification of proteins in single embryonic cells with neural fate in the cleavage-stage frog (Xenopus laevis) embryo using capillary electrophoresis electrospray ionization high-resolution mass spectrometry (CE-ESI-HRMS). Mol Cell Proteomics 15(8):2756–2768

    Google Scholar 

  • López de Laorden C, Beloqui A, Yate L, Calvo J, Puigivila M, Llop J, Reichardt N (2014) Nanostructured indium tin oxide slides for small-molecule profiling and imaging mass spectrometry of metabolites by surface-assisted laser desorption ionization MS. Anal Chem 87(1):431–440

    Google Scholar 

  • Macaulay I, Voet T (2014) Single cell genomics: advances and future perspectives. PLoS Genet 10(1):e1004126

    Google Scholar 

  • Managh A, Edwards S, Bushell A, Wood K, Geissler E, Hutchinson J, Hutchinson R, Reid H, Sharp B (2013) Single cell tracking of gadolinium labeled CD4+ T cells by laser ablation inductively coupled plasma mass spectrometry. Anal Chem 85(22):10627–10634

    Google Scholar 

  • Mandal M, Chen L, Hiraoka K (2011) Sequential and exhaustive ionization of analytes with different surface activity by probe electrospray ionization. J Am Soc Mass Spectrom 22(9): 1493–1500

    Google Scholar 

  • Mandal M, Saha S, Yoshimura K, Shida Y, Takeda S, Nonami H, Hiraoka K (2013) Biomolecular analysis and cancer diagnostics by negative mode probe electrospray ionization. Analyst 138(6):1682

    Google Scholar 

  • Miyashita S, Groombridge A, Fujii S, Takatsu A, Chiba K, Inagaki K (2014) Time-resolved ICP-MS measurement: a new method for elemental and multiparametric analysis of single cells. Anal Sci 30(2):219–224

    Google Scholar 

  • Navas-Moreno M, Chan J (2018) Laser tweezers Raman microspectroscopy of single cells and biological particles. Methods Mol Biol 1745:219–257

    Google Scholar 

  • Nemes P, Barton A, Li Y, Vertes A (2008) Ambient molecular imaging and depth profiling of live tissue by infrared laser ablation electrospray ionization mass spectrometry. Anal Chem 80(12):4575–4582

    Google Scholar 

  • Oikawa A, Saito K (2012) Metabolite analyses of single cells. Plant J 70(1):30–38

    Google Scholar 

  • Ong T, Tillmaand E, Makurath M, Rubakhin S, Sweedler J (2015) Mass spectrometry-based characterization of endogenous peptides and metabolites in small volume samples. Biochim Biophys Acta Proteins Proteomics 1854(7):732–740

    Google Scholar 

  • Onjiko R, Morris S, Moody S, Nemes P (2016) Single-cell mass spectrometry with multi-solvent extraction identifies metabolic differences between left and right blastomeres in the 8-cell frog (Xenopus) embryo. Analyst 141(12):3648–3656

    Google Scholar 

  • Onjiko R, Plotnick D, Moody S, Nemes P (2017) Metabolic comparison of dorsal versus ventral cells directly in the live 8-cell frog embryo by microprobe single-cell CE-ESI-MS. Anal Methods 9(34):4964–4970

    Google Scholar 

  • Pan N, Rao W, Kothapalli N, Liu R, Burgett A, Yang Z (2014) The single-probe: a miniaturized multifunctional device for single cell mass spectrometry analysis. Anal Chem 86(19): 9376–9380

    Google Scholar 

  • Paulsson K (2013) Genomic heterogeneity in acute leukemia. Cytogenet Genome Res 139(3): 174–180

    Google Scholar 

  • Pezzotti G, Horiguchi S, Boschetto F, Adachi T, Marin E, Zhu W, Yamamoto T, Kanamura N, Ohgitani E, Mazda O (2018) Raman imaging of individual membrane lipids and deoxynucleoside triphosphates in living neuronal cells during neurite outgrowth. ACS Chem Neurosci 9(12):3038–3048

    Google Scholar 

  • Piotto C, Guella G, Bettotti P (2017) Fluorinated surfaces: smart substrates for matrix-free laser desorption ionization. Rapid Commun Mass Spectrom 31(14):1228–1230

    Google Scholar 

  • Polat A, Özlü N (2014) Towards single-cell LC-MS phosphoproteomics. Analyst 139(19): 4733–4749

    Google Scholar 

  • Qureshi M, Stecher G, Bonn G (2013) Matrix free material enhanced laser desorption ionization mass spectrometric analysis of amino acids in Althaea officinalis, Matricaria chamomilla, and Taraxacum officinale. Anal Lett 46(1):29–34

    Google Scholar 

  • Ren S, Qu M, Sun Y (2013) Investigating intratumour heterogeneity by single-cell sequencing. Asian J Androl 15(6):729–734

    Google Scholar 

  • Å ala M, Å elih V, van Elteren J (2017) Gelatin gels as multi-element calibration standards in LA-ICP-MS bioimaging: fabrication of homogeneous standards and microhomogeneity testing. Analyst 142(18):3356–3359

    Google Scholar 

  • Schmid A, Neubauer P (2010) Analytical biotechnology: from single molecule and single cell analyses to population dynamics of metabolites and cells. Curr Opin Biotechnol 21(1):1–3

    Google Scholar 

  • Sirikatitham A, Yamamoto T, Shimizu M, Hasegawa T, Tsuyama N, Masujima T (2007) Resin-packed nanoelectrospray in combination with video and mass spectrometry for the direct and real-time molecular analysis of mast cells. Rapid Commun Mass Spectrom 21(3):385–390

    Google Scholar 

  • Sodhi R (2004) Time-of-flight secondary ion mass spectrometry (TOF-SIMS): versatility in chemical and imaging surface analysis. Analyst 129(6):483–487

    Google Scholar 

  • Speich M, Pineau A, Ballereau F (2001) Minerals, trace elements and related biological variables in athletes and during physical activity. Clin Chim Acta 312(1–2):1–11

    Google Scholar 

  • Takats Z, Wiseman J, Gologan B, Cooks R (2004) Mass spectrometry sampling under ambient conditions with desorption electrospray ionization. Science 306(5695):471–473

    Google Scholar 

  • Taylor A, Graham D, Castner D (2015) Reconstructing accurate ToF-SIMS depth profiles for organic materials with differential sputter rates. Analyst 140(17):6005–6014

    Google Scholar 

  • Tjalkens R, Carbone D, Wu G (2011) Detection of nitric oxide formation in primary neural cells and tissues. Methods Mol Biol 758:267–277

    Google Scholar 

  • Urban P, Schmid T, Amantonico A, Zenobi R (2011) Multidimensional analysis of single algal cells by integrating microspectroscopy with mass spectrometry. Anal Chem 83(5):1843–1849

    Google Scholar 

  • von Muhlen M, Brault N, Knudsen S, Jiang S, Manalis S (2010) Label-free biomarker sensing in undiluted serum with suspended microchannel resonators. Anal Chem 82(5):1905–1910

    Google Scholar 

  • Voras Z, deGhetaldi K, Wiggins M, Buckley B, Baade B, Mass J, Beebe T (2015) ToF–SIMS imaging of molecular-level alteration mechanisms in Le Bonheur de vivre by Henri Matisse. Appl Phys A 121(3):1015–1030

    Google Scholar 

  • Wang H, Wu Z, Chen B, He M, Hu B (2015) Chip-based array magnetic solid phase microextraction on-line coupled with inductively coupled plasma mass spectrometry for the determination of trace heavy metals in cells. Analyst 140(16):5619–5626

    Google Scholar 

  • Wishart D, Tzur D, Knox C, Eisner R, Guo A, Young N, Cheng D, Jewell K, Arndt D, Sawhney S, Fung C, Nikolai L, Lewis M, Coutouly M, Forsythe I, Tang P, Shrivastava S, Jeroncic K, Stothard P, Amegbey G, Block D, Hau D, Wagner J, Miniaci J, Clements M, Gebremedhin M, Guo N, Zhang Y, Duggan G, MacInnis G, Weljie A, Dowlatabadi R, Bamforth F, Clive D, Greiner R, Li L, Marrie T, Sykes B, Vogel H, Querengesser L (2007) HMDB: the human metabolome database. Nucleic Acids Res 35:D521–D526

    Google Scholar 

  • Xiong X, Zhang S, Fang X, Gong X, Zhang X (2016) Recent advances in mass spectrometry based single cell analysis methods. Sci Sin Chim 46(2):133–152

    Google Scholar 

  • Yang Y, Huang Y, Wu J, Liu N, Deng J, Luan T (2017) Single-cell analysis by ambient mass spectrometry. TrAC Trends Anal Chem 90:14–26

    Google Scholar 

  • Yin L, Zhang Z, Liu Y, Gao Y, Gu J (2019) Recent advances in single-cell analysis by mass spectrometry. Analyst 144(3):824–845

    Google Scholar 

  • Yokoyama Y, Aoyagi S, Shimanouchi T, Iwamura M, Iwai H (2016) ToF-SIMS analysis of amyloid beta aggregation on different lipid membranes. Biointerphases 11(2):02A314

    Google Scholar 

  • Yu L, Yao T, Ni S, Zeng S (2005) Determination of zolmitriptan enantiomers in rat liver microsomes by chiral high performance liquid chromatography with fluorescence detection. Biomed Chromatogr 19(3):191–195

    Google Scholar 

  • Yu Z, Chen L, Ninomiya S, Mandal M, Hiraoka K, Nonami H (2014) Piezoelectric inkjet assisted rapid electrospray ionization mass spectrometric analysis of metabolites in plant single cells via a direct sampling probe. Analyst 139(22):5734–5739

    Google Scholar 

  • Yuan F, Zhang D, Liu J, Zhou Y, Zhang X (2016) Phytochemical profiling in single plant cell by high performance liquid chromatography-mass spectrometry. Analyst 141(22):6338–6343

    Google Scholar 

  • Zabzdyr J, Lillard S (2001) UV- and visible-excited fluorescence of nucleic acids separated by capillary electrophoresis. J Chromatogr A 911(2):269–276

    Google Scholar 

  • Zenobi R (2013) Analytical and biological perspectives. Science 342(6163):1243259–1243259

    Google Scholar 

  • Zhang L, Vertes A (2018) Single-cell mass spectrometry approaches to explore cellular heterogeneity. Angew Chem Int Ed 57(17):4466–4477

    Google Scholar 

  • Zhang L, Qv S, Wang Z, Cheng J (2003) Determination of dopamine in single rat pheochromocytoma cell by capillary electrophoresis with amperometric detection. J Chromatogr B 792(2): 381–385

    Google Scholar 

  • Zhang X, Chen B, He M, Zhang Y, Peng L, Hu B (2016a) Boronic acid recognition based-gold nanoparticle-labeling strategy for the assay of sialic acid expression on cancer cell surface by inductively coupled plasma mass spectrometry. Analyst 141(4):1286–1293

    Google Scholar 

  • Zhang X, Wei Z, Gong X, Si X, Zhao Y, Yang C, Zhang S, Zhang X (2016b) Integrated droplet-based microextraction with ESI-MS for removal of matrix interference in single-cell analysis. Sci Rep 6(1):24730–24739

    Google Scholar 

  • Zhang J, Yan S, He Z, Ding C, Zhai T, Chen Y, Li H, Yang G, Zhou X, Wang P (2018) Small unnatural amino acid carried Raman tag for molecular imaging of genetically targeted proteins. J Phys Chem Lett 9(16):4679–4685

    Google Scholar 

  • Zheng X, Beard B, Johnson C (2018) Assessment of matrix effects associated with Fe isotope analysis using 266 nm femtosecond and 193 nm nanosecond laser ablation multi-collector inductively coupled plasma mass spectrometry. J Anal At Spectrom 33(1):68–83

    Google Scholar 

Download references

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2018R1A6A1A03025582 and 2019R1D1A3A03103828), Republic of Korea.

Author information

Authors and Affiliations

  1. Department of Biosystems Engineering, The Institute of Forest Science, Kangwon National University, Chuncheon, Republic of Korea

    Dinesh K. Patel, Sayan Deb Dutta & Ki-Taek Lim

Authors
  1. Dinesh K. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sayan Deb Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ki-Taek Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ki-Taek Lim .

Editor information

Editors and Affiliations

  1. Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India

    Tuhin Subhra Santra

  2. Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan

    Fan-Gang Tseng

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Patel, D.K., Dutta, S.D., Lim, KT. (2020). Mass Spectrometry for Single-Cell Analysis. In: Santra, T., Tseng, FG. (eds) Handbook of Single Cell Technologies. Springer, Singapore. https://doi.org/10.1007/978-981-10-4857-9_31-1

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-4857-9_31-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-4857-9

  • Online ISBN: 978-981-10-4857-9

  • eBook Packages: Springer Reference EngineeringReference Module Computer Science and Engineering

Publish with us

Policies and ethics

Search

Navigation