Abstract

In this work we demonstrate a label-free optical imaging technique to assess metabolic status and oxidative stress in human induced pluripotent stem cell-derived cardiomyocytes by two-photon fluorescence lifetime imaging of endogenous fluorophores. Our results show the sensitivity of this method to detect shifts in metabolism and oxidative stress in the cardiomyocytes upon pathological stimuli of hypoxia and cardiotoxic drugs. This non-invasive imaging technique could prove beneficial for drug development and screening, especially for in vitro cardiac models created from stem cell-derived cardiomyocytes and to study the pathogenesis of cardiac diseases and therapy.

© 2016 Optical Society of America

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    [Crossref] [PubMed]
  3. A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
    [Crossref] [PubMed]
  4. N. M. Mordwinkin, P. W. Burridge, and J. C. Wu, “A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards,” J. Cardiovasc. Transl. Res. 6(1), 22–30 (2013).
    [Crossref] [PubMed]
  5. N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Cardiomyocytes derived from human pluripotent stem cells for drug screening,” Pharmacol. Ther. 134(2), 180–188 (2012).
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  6. A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Res. Cardiol. 108(4), 359 (2013).
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
  17. R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
    [Crossref] [PubMed]
  18. M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
    [Crossref] [PubMed]
  19. J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
    [Crossref] [PubMed]
  20. T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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  25. B. O’Rourke, S. Cortassa, and M. A. Aon, “Mitochondrial ion channels: gatekeepers of life and death,” Physiology (Bethesda) 20(5), 303–315 (2005).
    [Crossref] [PubMed]
  26. E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH Fluorescence in Isolated Guinea-Pig and Rat Cardiomyocytes Exposed to Low or High Stimulation Rates and Effect of Metabolic Inhibition with Cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
    [Crossref] [PubMed]
  27. A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
    [Crossref] [PubMed]
  28. J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
    [Crossref] [PubMed]
  29. F. J. Giordano, “Oxygen, oxidative stress, hypoxia, and heart failure,” J. Clin. Invest. 115(3), 500–508 (2005).
    [Crossref] [PubMed]
  30. H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
    [Crossref] [PubMed]
  31. S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
    [Crossref] [PubMed]
  32. X. Zhou, X. Zhai, and M. Ashraf, “Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes,” Circulation 93(6), 1177–1184 (1996).
    [Crossref] [PubMed]
  33. K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
    [Crossref] [PubMed]
  34. X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
    [Crossref] [PubMed]

2015 (3)

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
[Crossref] [PubMed]

Z. V Varga, P. Ferdinandy, L. Liaudet, and P. Pacher, “Drug-induced mitochondrial dysfunction and cardiotoxicity,” Am. J. Physiol. 309, 00554 (2015).

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

2014 (3)

G. L. Semenza, “Hypoxia-inducible factor 1 and cardiovascular disease,” Annu. Rev. Physiol. 76(1), 39–56 (2014).
[Crossref] [PubMed]

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

2013 (4)

N. M. Mordwinkin, P. W. Burridge, and J. C. Wu, “A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards,” J. Cardiovasc. Transl. Res. 6(1), 22–30 (2013).
[Crossref] [PubMed]

A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Res. Cardiol. 108(4), 359 (2013).
[Crossref] [PubMed]

A. Colombo, C. Cipolla, M. Beggiato, and D. Cardinale, “Cardiac toxicity of anticancer agents,” Curr. Cardiol. Rep. 15(5), 362 (2013).
[Crossref] [PubMed]

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

2012 (8)

D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-Induced Oxidative Stress and Toxicity,” J. Toxicol. 2012, 645460 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

C. Stringari, R. Sierra, P. J. Donovan, and E. Gratton, “Label-free separation of human embryonic stem cells and their differentiating progenies by phasor fluorescence lifetime microscopy,” J. Biomed. Opt. 17(4), 046012 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah, “Redox signaling in cardiac physiology and pathology,” Circ. Res. 111(8), 1091–1106 (2012).
[Crossref] [PubMed]

I. Georgakoudi and K. P. Quinn, “Optical imaging using endogenous contrast to assess metabolic state,” Annu. Rev. Biomed. Eng. 14(1), 351–367 (2012).
[Crossref] [PubMed]

N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Cardiomyocytes derived from human pluripotent stem cells for drug screening,” Pharmacol. Ther. 134(2), 180–188 (2012).
[Crossref] [PubMed]

2011 (2)

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
[Crossref] [PubMed]

2010 (2)

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

A. A. Heikal, “Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies,” Biomarkers Med. 4(2), 241–263 (2010).
[Crossref] [PubMed]

2009 (1)

V. V. Ghukasyan and F.-J. Kao, “Monitoring Cellular Metabolism with Fluorescence Lifetime of Reduced Nicotinamide Adenine Dinucleotide †,” J. Phys. Chem. C 113(27), 11532–11540 (2009).
[Crossref]

2008 (1)

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

2007 (2)

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

2005 (4)

F. J. Giordano, “Oxygen, oxidative stress, hypoxia, and heart failure,” J. Clin. Invest. 115(3), 500–508 (2005).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

B. O’Rourke, S. Cortassa, and M. A. Aon, “Mitochondrial ion channels: gatekeepers of life and death,” Physiology (Bethesda) 20(5), 303–315 (2005).
[Crossref] [PubMed]

1998 (3)

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH Fluorescence in Isolated Guinea-Pig and Rat Cardiomyocytes Exposed to Low or High Stimulation Rates and Effect of Metabolic Inhibition with Cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

1996 (1)

X. Zhou, X. Zhai, and M. Ashraf, “Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes,” Circulation 93(6), 1177–1184 (1996).
[Crossref] [PubMed]

Albini, A.

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

Alfonso-García, A.

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
[Crossref] [PubMed]

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

Aon, M. A.

B. O’Rourke, S. Cortassa, and M. A. Aon, “Mitochondrial ion channels: gatekeepers of life and death,” Physiology (Bethesda) 20(5), 303–315 (2005).
[Crossref] [PubMed]

Arteaga, C. L.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

Ashraf, M.

X. Zhou, X. Zhai, and M. Ashraf, “Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes,” Circulation 93(6), 1177–1184 (1996).
[Crossref] [PubMed]

Azarin, S. M.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Bao, X.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Becker, L. B.

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

Beggiato, M.

A. Colombo, C. Cipolla, M. Beggiato, and D. Cardinale, “Cardiac toxicity of anticancer agents,” Curr. Cardiol. Rep. 15(5), 362 (2013).
[Crossref] [PubMed]

Binah, O.

N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Cardiomyocytes derived from human pluripotent stem cells for drug screening,” Pharmacol. Ther. 134(2), 180–188 (2012).
[Crossref] [PubMed]

Bird, D. K.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Burgoyne, J. R.

J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah, “Redox signaling in cardiac physiology and pathology,” Circ. Res. 111(8), 1091–1106 (2012).
[Crossref] [PubMed]

Burridge, P. W.

N. M. Mordwinkin, P. W. Burridge, and J. C. Wu, “A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards,” J. Cardiovasc. Transl. Res. 6(1), 22–30 (2013).
[Crossref] [PubMed]

Caiolfa, V. R.

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Cammarota, R.

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

Cardinale, D.

A. Colombo, C. Cipolla, M. Beggiato, and D. Cardinale, “Cardiac toxicity of anticancer agents,” Curr. Cardiol. Rep. 15(5), 362 (2013).
[Crossref] [PubMed]

Chandel, N. S.

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

Choi, A. M. K.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Cinco, R.

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
[Crossref] [PubMed]

Cipolla, C.

A. Colombo, C. Cipolla, M. Beggiato, and D. Cardinale, “Cardiac toxicity of anticancer agents,” Curr. Cardiol. Rep. 15(5), 362 (2013).
[Crossref] [PubMed]

Colombo, A.

A. Colombo, C. Cipolla, M. Beggiato, and D. Cardinale, “Cardiac toxicity of anticancer agents,” Curr. Cardiol. Rep. 15(5), 362 (2013).
[Crossref] [PubMed]

Cook, R. S.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

Cortassa, S.

B. O’Rourke, S. Cortassa, and M. A. Aon, “Mitochondrial ion channels: gatekeepers of life and death,” Physiology (Bethesda) 20(5), 303–315 (2005).
[Crossref] [PubMed]

Datta, R.

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
[Crossref] [PubMed]

De Flora, S.

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

Deavall, D. G.

D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-Induced Oxidative Stress and Toxicity,” J. Toxicol. 2012, 645460 (2012).
[Crossref] [PubMed]

Digman, M. A.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Donatelli, F.

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

Donovan, P. J.

C. Stringari, R. Sierra, P. J. Donovan, and E. Gratton, “Label-free separation of human embryonic stem cells and their differentiating progenies by phasor fluorescence lifetime microscopy,” J. Biomed. Opt. 17(4), 046012 (2012).
[Crossref] [PubMed]

Duranteau, J.

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

Eaton, P.

J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah, “Redox signaling in cardiac physiology and pathology,” Circ. Res. 111(8), 1091–1106 (2012).
[Crossref] [PubMed]

Edwards, R. A.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Eliceiri, K. W.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Ferdinandy, P.

Z. V Varga, P. Ferdinandy, L. Liaudet, and P. Pacher, “Drug-induced mitochondrial dysfunction and cardiotoxicity,” Am. J. Physiol. 309, 00554 (2015).

Freudiger, C. W.

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
[Crossref] [PubMed]

Garner, C.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Georgakoudi, I.

I. Georgakoudi and K. P. Quinn, “Optical imaging using endogenous contrast to assess metabolic state,” Annu. Rev. Biomed. Eng. 14(1), 351–367 (2012).
[Crossref] [PubMed]

George, S. C.

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

Ghukasyan, V. V.

V. V. Ghukasyan and F.-J. Kao, “Monitoring Cellular Metabolism with Fluorescence Lifetime of Reduced Nicotinamide Adenine Dinucleotide †,” J. Phys. Chem. C 113(27), 11532–11540 (2009).
[Crossref]

Giordano, F. J.

F. J. Giordano, “Oxygen, oxidative stress, hypoxia, and heart failure,” J. Clin. Invest. 115(3), 500–508 (2005).
[Crossref] [PubMed]

Gratton, E.

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
[Crossref] [PubMed]

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

C. Stringari, R. Sierra, P. J. Donovan, and E. Gratton, “Label-free separation of human embryonic stem cells and their differentiating progenies by phasor fluorescence lifetime microscopy,” J. Biomed. Opt. 17(4), 046012 (2012).
[Crossref] [PubMed]

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Griffiths, E. J.

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH Fluorescence in Isolated Guinea-Pig and Rat Cardiomyocytes Exposed to Low or High Stimulation Rates and Effect of Metabolic Inhibition with Cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

Hafstad, A. D.

A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Res. Cardiol. 108(4), 359 (2013).
[Crossref] [PubMed]

Hallworth, R.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Hazeltine, L. B.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Hecht, C.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Heikal, A. A.

A. A. Heikal, “Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies,” Biomarkers Med. 4(2), 241–263 (2010).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

Heylman, C.

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

Hicks, D. J.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

Hoetzel, A.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Hong, H.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Horner, J. M.

D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-Induced Oxidative Stress and Toxicity,” J. Toxicol. 2012, 645460 (2012).
[Crossref] [PubMed]

Hoverter, N. P.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Hsiao, C.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Hughes, C. C.

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

Ikonen, E.

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

Itskovitz-Eldor, J.

N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Cardiomyocytes derived from human pluripotent stem cells for drug screening,” Pharmacol. Ther. 134(2), 180–188 (2012).
[Crossref] [PubMed]

Kamp, T. J.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Kao, F.-J.

V. V. Ghukasyan and F.-J. Kao, “Monitoring Cellular Metabolism with Fluorescence Lifetime of Reduced Nicotinamide Adenine Dinucleotide †,” J. Phys. Chem. C 113(27), 11532–11540 (2009).
[Crossref]

Kasischke, K. A.

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

Keely, P. J.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Kim, H. P.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Kulisz, A.

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

Kunisada, T.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Lafontant, A.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

Li, C.

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

Lian, X.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Liaudet, L.

Z. V Varga, P. Ferdinandy, L. Liaudet, and P. Pacher, “Drug-induced mitochondrial dysfunction and cardiotoxicity,” Am. J. Physiol. 309, 00554 (2015).

Lin, H.

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH Fluorescence in Isolated Guinea-Pig and Rat Cardiomyocytes Exposed to Low or High Stimulation Rates and Effect of Metabolic Inhibition with Cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

Manning, H. C.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

Marquardt, M. M.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Martin, E. A.

D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-Induced Oxidative Stress and Toxicity,” J. Toxicol. 2012, 645460 (2012).
[Crossref] [PubMed]

Matsumura, Y.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

McQuade, M. M.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Min, W.

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
[Crossref] [PubMed]

Mongue-Din, H.

J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah, “Redox signaling in cardiac physiology and pathology,” Circ. Res. 111(8), 1091–1106 (2012).
[Crossref] [PubMed]

Mordwinkin, N. M.

N. M. Mordwinkin, P. W. Burridge, and J. C. Wu, “A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards,” J. Cardiovasc. Transl. Res. 6(1), 22–30 (2013).
[Crossref] [PubMed]

Morizane, A.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Nabeebaccus, A. A.

A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Res. Cardiol. 108(4), 359 (2013).
[Crossref] [PubMed]

Nakagawa, M.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Nakahira, K.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Nichols, M. G.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Noonan, D. M.

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

O’Rourke, B.

B. O’Rourke, S. Cortassa, and M. A. Aon, “Mitochondrial ion channels: gatekeepers of life and death,” Physiology (Bethesda) 20(5), 303–315 (2005).
[Crossref] [PubMed]

Okada, A.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Okamoto, S.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Okita, K.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Pacher, P.

Z. V Varga, P. Ferdinandy, L. Liaudet, and P. Pacher, “Drug-induced mitochondrial dysfunction and cardiotoxicity,” Am. J. Physiol. 309, 00554 (2015).

Palecek, S. P.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Park, J. W.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Pate, K. T.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Pennesi, G.

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
[Crossref] [PubMed]

Pfisterer, S. G.

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

Potma, E. O.

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

Quinn, K. P.

I. Georgakoudi and K. P. Quinn, “Optical imaging using endogenous contrast to assess metabolic state,” Annu. Rev. Biomed. Eng. 14(1), 351–367 (2012).
[Crossref] [PubMed]

Ramanujam, N.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Riching, K. M.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Riezman, H.

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

Roberts, R.

D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-Induced Oxidative Stress and Toxicity,” J. Toxicol. 2012, 645460 (2012).
[Crossref] [PubMed]

Ruvkun, G.

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
[Crossref] [PubMed]

Ryter, S. W.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Saji, H.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Sato, Y.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Schumacker, P. T.

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

Semenza, G. L.

G. L. Semenza, “Hypoxia-inducible factor 1 and cardiovascular disease,” Annu. Rev. Physiol. 76(1), 39–56 (2014).
[Crossref] [PubMed]

Shah, A. M.

A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Res. Cardiol. 108(4), 359 (2013).
[Crossref] [PubMed]

J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah, “Redox signaling in cardiac physiology and pathology,” Circ. Res. 111(8), 1091–1106 (2012).
[Crossref] [PubMed]

Shao, Z.

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

Shibata, T.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Shirure, V. S.

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

Sierra, R.

C. Stringari, R. Sierra, P. J. Donovan, and E. Gratton, “Label-free separation of human embryonic stem cells and their differentiating progenies by phasor fluorescence lifetime microscopy,” J. Biomed. Opt. 17(4), 046012 (2012).
[Crossref] [PubMed]

Skala, M. C.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Sobrino, A.

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

Sprowl-Tanio, S.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Stringari, C.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

C. Stringari, R. Sierra, P. J. Donovan, and E. Gratton, “Label-free separation of human embryonic stem cells and their differentiating progenies by phasor fluorescence lifetime microscopy,” J. Biomed. Opt. 17(4), 046012 (2012).
[Crossref] [PubMed]

Suleiman, M. S.

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH Fluorescence in Isolated Guinea-Pig and Rat Cardiomyocytes Exposed to Low or High Stimulation Rates and Effect of Metabolic Inhibition with Cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

Takahashi, J.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Takahashi, M.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Tanabe, K.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Teitell, M. A.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

TeSlaa, T.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Tezuka, K.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Vanden Hoek, T. L.

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

Varga, Z. V

Z. V Varga, P. Ferdinandy, L. Liaudet, and P. Pacher, “Drug-induced mitochondrial dysfunction and cardiotoxicity,” Am. J. Physiol. 309, 00554 (2015).

Vaughan, E. M.

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Vergen, J.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Vishwasrao, H. D.

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

Vrotsos, K. M.

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Walsh, A. J.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

Wang, K.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Wang, M. C.

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
[Crossref] [PubMed]

Wang, X.

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Waterman, M. L.

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Webb, W. W.

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

White, J. G.

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Wu, J. C.

N. M. Mordwinkin, P. W. Burridge, and J. C. Wu, “A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards,” J. Cardiovasc. Transl. Res. 6(1), 22–30 (2013).
[Crossref] [PubMed]

Xie, X. S.

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
[Crossref] [PubMed]

Yamanaka, S.

K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
[Crossref] [PubMed]

Yan, L.

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Zamai, M.

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Zeevi-Levin, N.

N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Cardiomyocytes derived from human pluripotent stem cells for drug screening,” Pharmacol. Ther. 134(2), 180–188 (2012).
[Crossref] [PubMed]

Zhai, X.

X. Zhou, X. Zhai, and M. Ashraf, “Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes,” Circulation 93(6), 1177–1184 (1996).
[Crossref] [PubMed]

Zhang, J.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Zholudeva, L. V.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Zhou, X.

X. Zhou, X. Zhai, and M. Ashraf, “Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes,” Circulation 93(6), 1177–1184 (1996).
[Crossref] [PubMed]

Zhu, K.

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
[Crossref] [PubMed]

Am. J. Physiol. (1)

Z. V Varga, P. Ferdinandy, L. Liaudet, and P. Pacher, “Drug-induced mitochondrial dysfunction and cardiotoxicity,” Am. J. Physiol. 309, 00554 (2015).

Annu. Rev. Biomed. Eng. (1)

I. Georgakoudi and K. P. Quinn, “Optical imaging using endogenous contrast to assess metabolic state,” Annu. Rev. Biomed. Eng. 14(1), 351–367 (2012).
[Crossref] [PubMed]

Annu. Rev. Physiol. (1)

G. L. Semenza, “Hypoxia-inducible factor 1 and cardiovascular disease,” Annu. Rev. Physiol. 76(1), 39–56 (2014).
[Crossref] [PubMed]

Antioxid. Redox Signal. (1)

S. W. Ryter, H. P. Kim, A. Hoetzel, J. W. Park, K. Nakahira, X. Wang, and A. M. K. Choi, “Mechanisms of cell death in oxidative stress,” Antioxid. Redox Signal. 9(1), 49–89 (2007).
[Crossref] [PubMed]

Basic Res. Cardiol. (1)

A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Res. Cardiol. 108(4), 359 (2013).
[Crossref] [PubMed]

Biochem. Pharmacol. (1)

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH Fluorescence in Isolated Guinea-Pig and Rat Cardiomyocytes Exposed to Low or High Stimulation Rates and Effect of Metabolic Inhibition with Cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

Biomarkers Med. (1)

A. A. Heikal, “Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies,” Biomarkers Med. 4(2), 241–263 (2010).
[Crossref] [PubMed]

Biophys. J. (1)

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Cancer Res. (2)

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73(20), 6164–6174 (2013).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Circ. Res. (1)

J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah, “Redox signaling in cardiac physiology and pathology,” Circ. Res. 111(8), 1091–1106 (2012).
[Crossref] [PubMed]

Circulation (1)

X. Zhou, X. Zhai, and M. Ashraf, “Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes,” Circulation 93(6), 1177–1184 (1996).
[Crossref] [PubMed]

Curr. Cardiol. Rep. (1)

A. Colombo, C. Cipolla, M. Beggiato, and D. Cardinale, “Cardiac toxicity of anticancer agents,” Curr. Cardiol. Rep. 15(5), 362 (2013).
[Crossref] [PubMed]

EMBO J. (1)

K. T. Pate, C. Stringari, S. Sprowl-Tanio, K. Wang, T. TeSlaa, N. P. Hoverter, M. M. McQuade, C. Garner, M. A. Digman, M. A. Teitell, R. A. Edwards, E. Gratton, and M. L. Waterman, “Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer,” EMBO J. 33(13), 1454–1473 (2014).
[PubMed]

Exp. Biol. Med. (Maywood) (1)

C. Heylman, A. Sobrino, V. S. Shirure, C. C. Hughes, and S. C. George, “A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening,” Exp. Biol. Med. (Maywood) 239(9), 1240–1254 (2014).
[Crossref] [PubMed]

J. Biol. Chem. (3)

J. Duranteau, N. S. Chandel, A. Kulisz, Z. Shao, and P. T. Schumacker, “Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes,” J. Biol. Chem. 273(19), 11619–11624 (1998).
[Crossref] [PubMed]

T. L. Vanden Hoek, L. B. Becker, Z. Shao, C. Li, and P. T. Schumacker, “Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes,” J. Biol. Chem. 273(29), 18092–18098 (1998).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

J. Biomed. Opt. (3)

A. Alfonso-García, S. G. Pfisterer, H. Riezman, E. Ikonen, and E. O. Potma, “D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage,” J. Biomed. Opt. 21(6), 061003 (2015).
[Crossref] [PubMed]

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

C. Stringari, R. Sierra, P. J. Donovan, and E. Gratton, “Label-free separation of human embryonic stem cells and their differentiating progenies by phasor fluorescence lifetime microscopy,” J. Biomed. Opt. 17(4), 046012 (2012).
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J. Cardiovasc. Transl. Res. (1)

N. M. Mordwinkin, P. W. Burridge, and J. C. Wu, “A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards,” J. Cardiovasc. Transl. Res. 6(1), 22–30 (2013).
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J. Clin. Invest. (1)

F. J. Giordano, “Oxygen, oxidative stress, hypoxia, and heart failure,” J. Clin. Invest. 115(3), 500–508 (2005).
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J. Natl. Cancer Inst. (1)

A. Albini, G. Pennesi, F. Donatelli, R. Cammarota, S. De Flora, and D. M. Noonan, “Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention,” J. Natl. Cancer Inst. 102(1), 14–25 (2010).
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V. V. Ghukasyan and F.-J. Kao, “Monitoring Cellular Metabolism with Fluorescence Lifetime of Reduced Nicotinamide Adenine Dinucleotide †,” J. Phys. Chem. C 113(27), 11532–11540 (2009).
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D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-Induced Oxidative Stress and Toxicity,” J. Toxicol. 2012, 645460 (2012).
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Microsc. Microanal. (2)

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
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J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
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Nat. Methods (2)

M. C. Wang, W. Min, C. W. Freudiger, G. Ruvkun, and X. S. Xie, “RNAi screening for fat regulatory genes with SRS microscopy,” Nat. Methods 8(2), 135–138 (2011).
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K. Okita, Y. Matsumura, Y. Sato, A. Okada, A. Morizane, S. Okamoto, H. Hong, M. Nakagawa, K. Tanabe, K. Tezuka, T. Shibata, T. Kunisada, M. Takahashi, J. Takahashi, H. Saji, and S. Yamanaka, “A more efficient method to generate integration-free human iPS cells,” Nat. Methods 8(5), 409–412 (2011).
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Nat. Protoc. (1)

X. Lian, J. Zhang, S. M. Azarin, K. Zhu, L. B. Hazeltine, X. Bao, C. Hsiao, T. J. Kamp, and S. P. Palecek, “Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions,” Nat. Protoc. 8(1), 162–175 (2012).
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Pharmacol. Ther. (1)

N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Cardiomyocytes derived from human pluripotent stem cells for drug screening,” Pharmacol. Ther. 134(2), 180–188 (2012).
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Physiology (Bethesda) (1)

B. O’Rourke, S. Cortassa, and M. A. Aon, “Mitochondrial ion channels: gatekeepers of life and death,” Physiology (Bethesda) 20(5), 303–315 (2005).
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Sci. Rep. (1)

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015).
[Crossref] [PubMed]

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Figures (5)

Fig. 1
Fig. 1 FLIM detects shift of metabolism to glycolysis when subjected to potassium cyanide (KCN). (a) Lifetime phasor distribution of untreated (left panel) and 4mM KCN treated (right panel) hiPS-CMs. Black circles shows phasor fingerprint of pure free NADH in solution (0.4ns) and protein lactate dehydrogenase bound NADH, ‘LDH-bound NADH’ (3.4ns) . Blue line indicates the metabolic trajectory on phasor plot. (b) Fluorescence intensity image (left panel) of two hiPS-CMs (cell 1 and cell 2) before (top row) and after (bottom row) treatment with 4mM KCN excited at 740nm. Middle panel shows the NADH FLIM map of cell 1 and cell 2 before (top row) and after (bottom row). Right panel shows the total phasor distribution of the treated and untreated cells. The color scale white/yellow to red/pink represents linear increase of free to protein bound NADH ratio. To create the NADH FLIM map, this color scale was applied from point A to B of the phasor distribution, dividing it into 32 levels.
Fig. 2
Fig. 2 Shift in metabolism for 24 hours of hypoxia (a) Fluorescence intensity image (left panel) of clusters of hiPS-CMs under normal 20% oxygen condition (Area 1 and Area 2) and hiPS-CM under hypoxia, 1% oxygen (Area 3 and Area 4) . Right panel shows the corresponding NADH FLIM map. The color scale white/yellow to red/pink represents linear increase of free to protein bound NADH ratio between position A’ and B’ shown on the phasor plot (bottom panel) . (b) Top panel shows phasor distribution obtained from 3 three different regions of hiPS-CM clusters of about 10 cells each for the two oxygen conditions. Bottom panel is quantitative representation of the fraction of pixels with phasors within the ‘low free/bound NADH’ (pink) window and the ‘high free/bound NADH’ (cyan) window (top panel). The windows divide the NADH phasor distribution equally at the center of mass of the NADH phasor distribution of the control cells (normoxia). The error bars show the standard deviation calculated over average value obtained from each image.
Fig. 3
Fig. 3 Significant increase in the long lifetime species (LLS) with hypoxia. (a) Top row panels shows fluorescent intensity image of hiPS-CM clusters under normoxia, 24 hours hypoxia, 48 hours hypoxia. Middle row panels show LLS FLIM map (in red) created by the LLS window in (b) top panel. Bottom row shows the corresponding individual phasor plots. (b) Top panel is the phasor distribution of 3 three different regions of hiPS-CM clusters, about 10 cells each for normoxia, 24 hours hypoxia, and 48 hours hypoxia conditions. Gray dotted window (‘Total NADH’) selects the total NADH distribution which covers the total area within pink and cyan windows of Fig. 2(b). ‘LLS’ window (red square) selects the LLS phasor distribution. Red dotted arrow indicated the oxidative stress axis. Bottom panel shows quantitative representation of the percentage pixels with lifetime phasors within the ‘Total NADH’ window (gray dotted rectangle) and ‘LLS’ phasor window (red square) of hiPS-CMs under normoxia, 24 hours hypoxia, and 48 hours hypoxia. The error bars shows the standard deviation calculated over average value obtained from each image. Statistical significance was computed by ANOVA with post-hoc Bonferroni correction.
Fig. 4
Fig. 4 Hyperspectral stimulated Raman scattering (SRS) scan of hiPS- CM exposed to 48 hours hypoxia, covering the CH stretching Raman band (2800 - 3050 cm−1) confirms association to lipid droplets. (a) SRS image at 2845cm−1 (CH2 symmetric stretching) characteristic of lipids. (b) Result of 3 endmember vertex component analysis (VCA). The red and blue show the normalized spectra of the 2 major endmembers retrieved. (c) Pseudo-colored VCA image of the SRS hyperspectral scan. The red spectrum is characteristic of lipids. It co-localizes with the lipid droplets observed in (a). The blue spectra have the features of the protein matrix that fills the cellular cytoplasm.
Fig. 5
Fig. 5 LLS produced by cardiotoxic drugs 3′-Azido-3′-deoxythymidine (AZT) and cis-Diamineplatinum(II) dichloride (cisplatin). (a) Top panel shows LLS FLIM map (in red) of hiPS-CM clusters (control, AZT treated and cisplatin treated). The FLIM map is generated by the LLS window (red square) selecting the characteristic long lifetime as shown on phasor plot (middle panel). Bottom panel shows the percentage pixels for control, AZT treated and cisplatin treated cells with lifetime phasors within the LLS phasor window. The scale bar is 20µm. (b) Top panel shows confocal image (control, AZT treated and cisplatin treated cells) of ROS indicator CellROX, excited at 633nm and signal collected within 640-740 nm. The scale bar is 200µm. Bottom panel shows the corresponding image intensity histogram.

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