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Analytical techniques for single-cell metabolomics: state of the art and trends

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Abstract

Single-cell metabolomics is an emerging field that addresses fundamental biological questions and allows one to observe metabolic phenomena in heterogeneous populations of single cells. In this review, we assess the suitability of different detection techniques and present considerations on sample preparation for single-cell metabolomics. Although targeted analysis of single cells can readily be conducted using fluorescent probes and optical instruments (microscopes, fluorescence detectors), a comprehensive metabolomic approach requires a powerful label-free method, such as mass spectrometry (MS). Mass-spectrometric techniques applied to study small molecules in single cells include electrospray MS, matrix-assisted laser desorption/ionization MS, and secondary ion MS. Sample preparation is an important aspect to be taken into account during further development of methods for single-cell metabolomics.

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References

  1. Hollywood K, Brison DR, Goodacre R (2006) Proteomics 6:4716–4723

    Article  CAS  Google Scholar 

  2. Ryan D, Robards K (2006) Anal Chem 78:7954–7958

    Article  CAS  Google Scholar 

  3. Blow N (2008) Nature 455:697–700

    Article  CAS  Google Scholar 

  4. Dunn WB, Bailey NJ, Johnson HE (2005) Analyst 130:606–625

    Article  CAS  Google Scholar 

  5. Bennett BD, Kimball EH, Gao M, Osterhout R, Van Dien SJ, Rabinowitz JD (2009) Nat Chem Biol 5:593–599

    Article  CAS  Google Scholar 

  6. Diks SH, Peppelenbosch MP (2004) Trends Mol Med 10:574–577

    Article  CAS  Google Scholar 

  7. Davidson CJ, Surette MG (2008) Annu Rev Genet 42:253–268

    Article  CAS  Google Scholar 

  8. Lange BM (2005) Curr Opin Plant Biol 8:236–241

    Article  CAS  Google Scholar 

  9. Locke JC, Elowitz MB (2009) Nat Rev Microbiol 7:383–392

    Article  CAS  Google Scholar 

  10. Walker A, Parkhill J (2008) Nat Rev Microbiol 6:176–177

    Article  CAS  Google Scholar 

  11. Zeng Y, Novak R, Shuga J, Smith MT, Mathies RA (2010) Anal Chem 82:3183–3190

    Article  CAS  Google Scholar 

  12. Zhang K, Martiny AC, Reppas NB, Barry KW, Malek J, Chisholm SW, Church GM (2006) Nat Biotechnol 24:680–686

    Article  CAS  Google Scholar 

  13. Cai L, Friedman N, Xie XS (2006) Nature 440:358–362

    Article  CAS  Google Scholar 

  14. Choi PJ, Cai L, Frieda K, Xie XS (2008) Science 322:442–446

    Article  CAS  Google Scholar 

  15. Cohen D, Dickerson JA, Whitmore CD, Turner EH, Palcic MM, Hindsgaul O, Dovichi NJ (2008) Annu Rev Anal Chem 1:165–190

    Article  CAS  Google Scholar 

  16. Gutstein HB, Morris JS, Annangudi SP, Sweedler JV (2008) Mass Spectrom Rev 27:316–330

    Article  CAS  Google Scholar 

  17. Huang B, Wu H, Bhaya D, Grossman A, Granier S, Kobilka BK, Zare RN (2007) Science 315:81–84

    Article  CAS  Google Scholar 

  18. Newman JR, Ghaemmaghami S, Ihmels J, Breslow DK, Noble M, DeRisi JL, Weissman JS (2006) Nature 441:840–846

    Article  CAS  Google Scholar 

  19. Raj A, van Oudenaarden A (2008) Cell 135:216–226

    Article  CAS  Google Scholar 

  20. Raser JM, O'Shea EK (2004) Science 304:1811–1814

    Article  CAS  Google Scholar 

  21. Shim JU, Olguin LF, Whyte G, Scott D, Babtie A, Abell C, Huck WT, Hollfelder F (2009) J Am Chem Soc 131:15251–15256

    Article  CAS  Google Scholar 

  22. Borland LM, Kottegoda S, Phillips KS, Allbritton NL (2008) Annu Rev Anal Chem 1:191–227

    Article  CAS  Google Scholar 

  23. Anselmetti D (ed) (2009) Single cell analysis: technologies and applications. Wiley-VCH, Weinheim

    Google Scholar 

  24. Lu C (ed) (2010) Chemical cytometry: ultrasensitive analysis of single cells. Wiley-VCH, Weinheim

    Google Scholar 

  25. An GH, Suh OS, Kwon HC, Kim K, Johnson EA (2000) Biotechnol Lett 22:1031–1034

    Article  CAS  Google Scholar 

  26. Berg J, Hung YP, Yellen G (2009) Nat Meth 6:161–166

    Article  CAS  Google Scholar 

  27. Chang HT, Yeung ES (1995) Anal Chem 67:1079–1083

    Article  CAS  Google Scholar 

  28. Fehr M, Frommer WB, Lalonde S (2002) Proc Natl Acad Sci USA 99:9846–9851

    Article  CAS  Google Scholar 

  29. Fuller RR, Moroz LL, Gillette R, Sweedler JV (1998) Neuron 20:173–181

    Article  CAS  Google Scholar 

  30. Moro AJ, Cywinski PJ, Korsten S, Mohr GJ (2010) Chem Commun 1085–1087

  31. Secrist JA 3rd, Barrio JR, Leonard NJ (1972) Science 175:646–647

    Article  CAS  Google Scholar 

  32. Williams C (2004) Nat Rev Drug Discov 3:125–135

    Article  CAS  Google Scholar 

  33. Okumoto S, Looger LL, Micheva KD, Reimer RJ, Smith SJ, Frommer WB (2005) Proc Natl Acad Sci USA 102:8740–8745

    Article  CAS  Google Scholar 

  34. Davey HM, Kell DB (1996) Microbiol Rev 60:641–696

    CAS  Google Scholar 

  35. Srisa-Art M, Bonzani IC, Williams A, Stevens MM, DeMello AJ, Edel JB (2009) Analyst 134:2239–2245

    Article  CAS  Google Scholar 

  36. Kennedy RT, Oates MD, Cooper BR, Nickerson B, Jorgenson JW (1989) Science 246:57–63

    Article  CAS  Google Scholar 

  37. Lapainis T, Scanlan C, Rubakhin SS, Sweedler JV (2007) Anal Bioanal Chem 387:97–105

    Article  CAS  Google Scholar 

  38. Xie W, Xu A, Yeung ES (2009) Anal Chem 81:1280–1284

    Article  CAS  Google Scholar 

  39. Whitmore CD, Hindsgaul O, Palcic MM, Schnaar RL, Dovichi NJ (2007) Anal Chem 79:5139–5142

    Article  CAS  Google Scholar 

  40. Wu H, Wheeler A, Zare RN (2004) Proc Natl Acad Sci USA 101:12809–12813

    Article  CAS  Google Scholar 

  41. Chen Z, Li Q, Wang X, Wang Z, Zhang R, Yin M, Yin L, Xu K, Tang B (2010) Anal Chem 82:2006–2012

    Article  CAS  Google Scholar 

  42. Huang L, Kennedy RT (1995) Trends Anal Chem 14:158–164

    Article  CAS  Google Scholar 

  43. Cannon DM Jr, Winograd N, Ewing AG (2000) Annu Rev Biophys Biomol Struct 29:239–263

    Article  CAS  Google Scholar 

  44. Kozminski KD, Gutman DA, Davila V, Sulzer D, Ewing AG (1998) Anal Chem 70:3123–3130

    Article  CAS  Google Scholar 

  45. Zhang B, Adams KL, Luber SJ, Eves DJ, Heien ML, Ewing AG (2008) Anal Chem 80:1394–1400

    Article  CAS  Google Scholar 

  46. Olefirowicz TM, Ewing AG (1990) Anal Chem 62:1872–1876

    Article  CAS  Google Scholar 

  47. Swanek FD, Chen GY, Ewing AG (1996) Anal Chem 68:3912–3916

    Article  CAS  Google Scholar 

  48. Weng QF, Jin WR (2003) Anal Chim Acta 478:199–207

    Article  CAS  Google Scholar 

  49. Jin W, Li X, Gao N (2003) Anal Chem 75:3859–3864

    Article  CAS  Google Scholar 

  50. Ai F, Chen H, Zhang SH, Liu SY, Wei F, Dong XY, Cheng JK, Huang WH (2009) Anal Chem 81:8453–8458

    Article  CAS  Google Scholar 

  51. Xia F, Jin W, Yin X, Fang Z (2005) J Chromatogr A 1063:227–233

    Article  CAS  Google Scholar 

  52. Dettmer K, Aronov PA, Hammock BD (2007) Mass Spectrom Rev 26:51–78

    Article  CAS  Google Scholar 

  53. Han J, Datla R, Chan S, Borchers C (2009) Bioanalysis 1:1665–1684

    Article  CAS  Google Scholar 

  54. Li L, Golding RE, Whittal RM (1996) J Am Chem Soc 118:11662–11663

    Article  CAS  Google Scholar 

  55. Romanova EV, Rubakhin SS, Monroe EB, Sweedler JV (2009) In: Anselmetti D (ed) Single cell analysis: technologies and applications. Weinheim, Wiley-VCH

    Google Scholar 

  56. Rubakhin SS, Sweedler JV (2007) Nat Protoc 2:1987–1997

    Article  CAS  Google Scholar 

  57. van Veelen PA, Jimenez CR, Li KW, Geraerts WPM, Tjaden UR, van der Greef J (1994) J Control Release 29:223–229

    Article  Google Scholar 

  58. Hillenkamp F, Peter-Katalinić J (2007) MALDI MS: a practical guide to instrumentation, methods and applications. Wiley-VCH, Weinheim

    Google Scholar 

  59. Karas M, Bachmann D, Bahr U, Hillenkamp F (1987) Int J Mass Spectrom Ion Process 78:53–68

    Article  CAS  Google Scholar 

  60. Edwards JL, Kennedy RT (2005) Anal Chem 77:2201–2209

    Article  CAS  Google Scholar 

  61. Nordstrom A, Want E, Northen T, Lehtio J, Siuzdak G (2008) Anal Chem 80:421–429

    Article  CAS  Google Scholar 

  62. Page JS, Rubakhin SS, Sweedler JV (2000) Analyst 125:555–561

    Article  CAS  Google Scholar 

  63. Rubakhin SS, Greenough WT, Sweedler JV (2003) Anal Chem 75:5374–5380

    Article  CAS  Google Scholar 

  64. Zimmerman TA, Rubakhin SS, Romanova EV, Tucker KR, Sweedler JV (2009) Anal Chem 81:9402–9409

    Article  CAS  Google Scholar 

  65. Amantonico A, Oh JY, Sobek J, Heinemann M, Zenobi R (2008) Angew Chem Int Ed 47:5382–5385

    Article  CAS  Google Scholar 

  66. Urban PL, Amantonico A, Fagerer SR, Gehrig P, Zenobi R (2010) Chem Commun 2212–2214

  67. Reyzer ML, Caprioli RM (2007) Curr Opin Chem Biol 11:29–35

    Article  CAS  Google Scholar 

  68. Benabdellah F, Touboul D, Brunelle A, Laprevote O (2009) Anal Chem 81:5557–5560

    Article  CAS  Google Scholar 

  69. Holscher D, Shroff R, Knop K, Gottschaldt M, Crecelius A, Schneider B, Heckel DG, Schubert US, Svatos A (2009) Plant J 60:907–918

    Article  CAS  Google Scholar 

  70. Jun JH, Song Z, Liu Z, Nikolau BJ, Yeung ES, Lee YJ (2010) Anal Chem 82:3255–3265

    Article  CAS  Google Scholar 

  71. Northen TR, Yanes O, Northen MT, Marrinucci D, Uritboonthai W, Apon J, Golledge SL, Nordstrom A, Siuzdak G (2007) Nature 449:1033–1036

    Article  CAS  Google Scholar 

  72. Shimizu M, Ojima N, Ohnishi H, Shingaki T, Hirakawa Y, Masujima T (2003) Anal Sci 19:49–53

    Article  CAS  Google Scholar 

  73. Mizuno H, Tsuyama N, Harada T, Masujima T (2008) J Mass Spectrom 43:1692–1700

    Article  CAS  Google Scholar 

  74. Shrestha B, Vertes A (2009) Anal Chem 81:8265–8271

    Article  CAS  Google Scholar 

  75. Lapainis T, Rubakhin SS, Sweedler JV (2009) Anal Chem 81:5858–5864

    Article  CAS  Google Scholar 

  76. Ostrowski SG, Kurczy ME, Roddy TP, Winograd N, Ewing AG (2007) Anal Chem 79:3554–3560

    Article  CAS  Google Scholar 

  77. Piehowski PD, Davey AM, Kurczy ME, Sheets ED, Winograd N, Ewing AG, Heien ML (2009) Anal Chem 81:5593–5602

    Article  CAS  Google Scholar 

  78. Gard E, Mayer JE, Morrical BD, Dienes T, Fergenson DP, Prather KA (1997) Anal Chem 69:4083–4091

    Article  CAS  Google Scholar 

  79. Tobias HJ, Pitesky ME, Fergenson DP, Steele PT, Horn J, Frank M, Gard EE (2006) J Microbiol Meth 67:56–63

    Article  CAS  Google Scholar 

  80. Lechene C, Hillion F, McMahon G, Benson D, Kleinfeld AM, Kampf JP, Distel D, Luyten Y, Bonventre J, Hentschel D, Park KM, Ito S, Schwartz M, Benichou G, Slodzian G (2006) J Biol 5:20

    Article  Google Scholar 

  81. Mcmahon G, Glassner BJ, Lechene CP (2006) Appl Surf Sci 252:6895–6906

    Article  CAS  Google Scholar 

  82. Kuypers MM, Jorgensen BB (2007) Environ Microbiol 9:6–7

    Article  Google Scholar 

  83. Orphan VJ, House CH, Hinrichs KU, McKeegan KD, DeLong EF (2001) Science 293:484–487

    Article  CAS  Google Scholar 

  84. Koek MM, Bakels F, Engel W, van den Maagdenberg A, Ferrari MD, Coulier L, Hankemeier T (2010) Anal Chem 82:156–162

    Article  CAS  Google Scholar 

  85. Fliermans CB, Schmidt EL (1975) Appl Microbiol 30:676–684

    CAS  Google Scholar 

  86. Cahill G, Walsh PK, Donnelly D (2000) Biotechnol Bioeng 69:312–322

    Article  CAS  Google Scholar 

  87. Shinohara H, Wang F (2007) Anal Sci 23:81–84

    Article  Google Scholar 

  88. Goff KL, Quaroni L, Wilson KE (2009) Analyst 134:2216–2219

    Article  CAS  Google Scholar 

  89. Buckmaster R, Asphahani F, Thein M, Xu J, Zhang M (2009) Analyst 134:1440–1446

    Article  CAS  Google Scholar 

  90. Hedegaard M, Krafft C, Ditzel HJ, Johansen LE, Hassing S, Popp J (2010) Anal Chem 82:2797–2802

    Article  CAS  Google Scholar 

  91. Hermelink A, Brauer A, Lasch P, Naumann D (2009) Analyst 134:1149–1153

    Article  CAS  Google Scholar 

  92. Schuster KC, Reese I, Urlaub E, Gapes JR, Lendl B (2000) Anal Chem 72:5529–5534

    Article  CAS  Google Scholar 

  93. Moritz TJ, Taylor DS, Polage CR, Krol DM, Lane SM, Chan JW (2010) Anal Chem 82:2703–2710

    Article  CAS  Google Scholar 

  94. Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC, Nicholson JK (2007) Nat Protoc 2:2692–2703

    Article  CAS  Google Scholar 

  95. Motta A, Paris D, Melck D (2010) Anal Chem 82:2405–2411

    Article  CAS  Google Scholar 

  96. Grant SC, Aiken NR, Plant HD, Gibbs S, Mareci TH, Webb AG, Blackband SJ (2000) Magn Reson Med 44:19–22

    Article  CAS  Google Scholar 

  97. Krojanski HG, Lambert J, Gerikalan Y, Suter D, Hergenroder R (2008) Anal Chem 80:8668–8672

    Article  CAS  Google Scholar 

  98. Canelas AB, ten Pierick A, Ras C, Seifar RM, van Dam JC, van Gulik WM, Heijnen JJ (2009) Anal Chem 81:7379–7389

    Article  CAS  Google Scholar 

  99. Winder CL, Dunn WB, Schuler S, Broadhurst D, Jarvis R, Stephens GM, Goodacre R (2008) Anal Chem 80:2939–2948

    Article  CAS  Google Scholar 

  100. Huang WH, Ai F, Wang ZL, Cheng JK (2008) J Chromatogr B 866:104–122

    Article  CAS  Google Scholar 

  101. Woods LA, Roddy TP, Ewing AG (2004) Electrophoresis 25:1181–1187

    Article  CAS  Google Scholar 

  102. El-Ali J, Sorger PK, Jensen KF (2006) Nature 442:403–411

    Article  CAS  Google Scholar 

  103. Le Gac S, van den Berg A (2010) Trends Biotechnol 28:55–62

    Article  CAS  Google Scholar 

  104. Price AK, Culbertson CT (2007) Anal Chem 79:2614–2621

    Article  CAS  Google Scholar 

  105. Roman GT, Chen Y, Viberg P, Culbertson AH, Culbertson CT (2007) Anal Bioanal Chem 387:9–12

    Article  CAS  Google Scholar 

  106. Yan H, Zhang B, Wu H (2008) Electrophoresis 29:1775–1786

    Article  CAS  Google Scholar 

  107. Pei J, Li Q, Lee MS, Valaskovic GA, Kennedy RT (2009) Anal Chem 81:6558–6561

    Article  CAS  Google Scholar 

  108. Fidalgo LM, Whyte G, Ruotolo BT, Benesch JL, Stengel F, Abell C, Robinson CV, Huck WT (2009) Angew Chem Int Ed 48:3665–3668

    Article  CAS  Google Scholar 

  109. Meister A, Gabi M, Behr P, Studer P, Voros J, Niedermann P, Bitterli J, Polesel-Maris J, Liley M, Heinzelmann H, Zambelli T (2009) Nano Lett 9:2501–2507

    Article  CAS  Google Scholar 

  110. Kraly JR, Holcomb RE, Guan Q, Henry CS (2009) Anal Chim Acta 653:23–35

    Article  CAS  Google Scholar 

  111. Moco S, Schneider B, Vervoort J (2009) J Proteome Res 8:1694–1703

    Article  CAS  Google Scholar 

  112. Brehm-Stecher BF, Johnson EA (2004) Microbiol Mol Biol Rev 68:538–559

    Article  CAS  Google Scholar 

  113. Dethlefsen L, Relman DA (2007) Environ Microbiol 9:8–10

    Article  Google Scholar 

  114. Mizuno H, Tsuyama N, Date S, Harada T, Masujima T (2008) Anal Sci 24:1525–1527

    Article  CAS  Google Scholar 

  115. Fung EN, Yeung ES (1998) Anal Chem 70:3206–3212

    Article  CAS  Google Scholar 

  116. Shimizu M, Levi-Schaffer F, Ojima N, Shingaki T, Masujima T (2002) Anal Sci 18:107–108

    Article  CAS  Google Scholar 

  117. Gholipour Y, Nonami H, Erra-Balsells R (2008) J Am Soc Mass Spectrom 19:1841–1848

    Article  CAS  Google Scholar 

  118. Rubakhin SS, Sweedler JV (2008) Anal Chem 80:7128–7136

    Article  CAS  Google Scholar 

  119. Fletcher JS, Rabbani S, Henderson A, Blenkinsopp P, Thompson SP, Lockyer NP, Vickerman JC (2008) Anal Chem 80:9058–9064

    Article  CAS  Google Scholar 

  120. Berman ES, Fortson SL, Checchi KD, Wu L, Felton JS, Wu KJ, Kulp KS (2008) J Am Soc Mass Spectrom 19:1230–1236

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Matthias Heinemann and Thomas Schmid for stimulating discussions. P.L.U. was funded by a Marie Curie Intra European Fellowship received within the Seventh European Community Framework Programme (contract no. PIEF-GA-2008-219222—MESEL).

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  1. Department of Chemistry and Applied Biosciences, ETH Zurich, 8093, Zurich, Switzerland

    Andrea Amantonico, Pawel L. Urban & Renato Zenobi

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  1. Andrea Amantonico
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  2. Pawel L. Urban
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  3. Renato Zenobi
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Correspondence to Renato Zenobi.

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Published in the special issue on Focus on Bioanalysis with guest editors Antje J. Baeumner, Günter Gauglitz, and Frieder W. Scheller.

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Amantonico, A., Urban, P.L. & Zenobi, R. Analytical techniques for single-cell metabolomics: state of the art and trends. Anal Bioanal Chem 398, 2493–2504 (2010). https://doi.org/10.1007/s00216-010-3850-1

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