Abstract

Megakaryopoiesis and platelet production are complex biological processes that require tight regulation of successive lineage commitment steps and are ultimately responsible for maintaining and renewing the pool of circulating platelets in the blood. Despite major advancements in the understanding of megakaryocytic biology, the detailed mechanisms driving megakaryocytic differentiation have yet to be elucidated. Here we show that automated image analysis algorithms applied to two-photon excited fluorescence (TPEF) images can non-invasively monitor structural and metabolic megakaryocyte behavior changes occurring during differentiation and platelet formation in vitro. Our results demonstrate that high-contrast, label-free two photon imaging holds great potential in studying the underlying physiological processes controlling the intricate process of platelet production.

© 2017 Optical Society of America

Full Article  |  PDF Article
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  1. A. E. Geddis, “Megakaryopoiesis,” Semin. Hematol. 47(3), 212–219 (2010).
    [Crossref] [PubMed]
  2. A. T. Franco, A. Corken, and J. Ware, “Platelets at the interface of thrombosis, inflammation, and cancer,” Blood 126(5), 582–588 (2015).
    [Crossref] [PubMed]
  3. K. Kaushansky, “The molecular mechanisms that control thrombopoiesis,” J. Clin. Invest. 115(12), 3339–3347 (2005).
    [Crossref] [PubMed]
  4. A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
    [Crossref] [PubMed]
  5. K. R. Machlus and J. E. Italiano., “The incredible journey: From megakaryocyte development to platelet formation,” J. Cell Biol. 201(6), 785–796 (2013).
    [Crossref] [PubMed]
  6. S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
    [Crossref] [PubMed]
  7. J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
    [Crossref] [PubMed]
  8. 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]
  9. K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
    [Crossref] [PubMed]
  10. A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
    [Crossref] [PubMed]
  11. M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
    [Crossref] [PubMed]
  12. M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev. 110(5), 2641–2684 (2010).
    [Crossref] [PubMed]
  13. K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
    [Crossref] [PubMed]
  14. T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
    [Crossref] [PubMed]
  15. A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
    [Crossref] [PubMed]
  16. D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
    [Crossref] [PubMed]
  17. N. Williams and R. F. Levine, “The origin, development and regulation of megakaryocytes,” Br. J. Haematol. 52(2), 173–180 (1982).
    [Crossref] [PubMed]
  18. I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
    [Crossref] [PubMed]
  19. 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]
  20. C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
    [Crossref] [PubMed]
  21. E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
    [Crossref] [PubMed]
  22. V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
    [Crossref] [PubMed]
  23. H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
    [Crossref] [PubMed]
  24. J. E. Italiano, P. Lecine, R. A. Shivdasani, and J. H. Hartwig, “Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes,” J. Cell Biol. 147(6), 1299–1312 (1999).
    [Crossref] [PubMed]
  25. A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
    [Crossref] [PubMed]
  26. M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
    [Crossref] [PubMed]
  27. D. M. Jameson, V. Thomas, and D. M. Zhou, “Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase,” Biochim. Biophys. Acta 994(2), 187–190 (1989).
    [Crossref] [PubMed]
  28. J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
    [Crossref] [PubMed]
  29. C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
    [Crossref] [PubMed]

2017 (1)

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

2016 (3)

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

2015 (3)

A. T. Franco, A. Corken, and J. Ware, “Platelets at the interface of thrombosis, inflammation, and cancer,” Blood 126(5), 582–588 (2015).
[Crossref] [PubMed]

J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
[Crossref] [PubMed]

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

2014 (2)

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

2013 (4)

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

K. R. Machlus and J. E. Italiano., “The incredible journey: From megakaryocyte development to platelet formation,” J. Cell Biol. 201(6), 785–796 (2013).
[Crossref] [PubMed]

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[Crossref] [PubMed]

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

2012 (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]

2011 (3)

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

2010 (2)

A. E. Geddis, “Megakaryopoiesis,” Semin. Hematol. 47(3), 212–219 (2010).
[Crossref] [PubMed]

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev. 110(5), 2641–2684 (2010).
[Crossref] [PubMed]

2009 (1)

I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
[Crossref] [PubMed]

2008 (3)

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]

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

2007 (1)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

2005 (1)

K. Kaushansky, “The molecular mechanisms that control thrombopoiesis,” J. Clin. Invest. 115(12), 3339–3347 (2005).
[Crossref] [PubMed]

1999 (1)

J. E. Italiano, P. Lecine, R. A. Shivdasani, and J. H. Hartwig, “Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes,” J. Cell Biol. 147(6), 1299–1312 (1999).
[Crossref] [PubMed]

1992 (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

1989 (1)

D. M. Jameson, V. Thomas, and D. M. Zhou, “Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase,” Biochim. Biophys. Acta 994(2), 187–190 (1989).
[Crossref] [PubMed]

1982 (1)

N. Williams and R. F. Levine, “The origin, development and regulation of megakaryocytes,” Br. J. Haematol. 52(2), 173–180 (1982).
[Crossref] [PubMed]

Abbonante, V.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Achilefu, S.

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev. 110(5), 2641–2684 (2010).
[Crossref] [PubMed]

Alonzo, C.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Alonzo, C. A.

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

Anselmo, A.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Balaban, R. S.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Balduini, A.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
[Crossref] [PubMed]

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Balduini, C.

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Balduini, C. L.

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Balu, M.

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

Barile, M.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Barosi, G.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Bender, M.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

Berezin, M. Y.

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev. 110(5), 2641–2684 (2010).
[Crossref] [PubMed]

Blinova, K.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Blundell, M. P.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Boja, E. S.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Busco, G.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (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]

Calaminus, S. D.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Carmone, C.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Celesti, G.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Cinquin, A.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Cinquin, O.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Colella, M.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Corken, A.

A. T. Franco, A. Corken, and J. Ware, “Platelets at the interface of thrombosis, inflammation, and cancer,” Blood 126(5), 582–588 (2015).
[Crossref] [PubMed]

Deschmann, E.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

Di Buduo, C. A.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Digman, M. A.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[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]

Dohda, T.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Donovan, P. J.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Ehrlicher, A. J.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Eliceiri, K. W.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Endo, H.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Eto, K.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Franco, A. T.

A. T. Franco, A. Corken, and J. Ware, “Platelets at the interface of thrombosis, inflammation, and cancer,” Blood 126(5), 582–588 (2015).
[Crossref] [PubMed]

Fujita, K.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Gachet, C.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Geddis, A. E.

A. E. Geddis, “Megakaryopoiesis,” Semin. Hematol. 47(3), 212–219 (2010).
[Crossref] [PubMed]

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Georgakoudi, I.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[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]

Giancaspero, T. A.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Gianelli, U.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Gong, Y.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

Gratton, E.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[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, G. L.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Gruppi, C.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

Harimoto, K.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Harris, R. M.

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

Hartwig, J. H.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

J. E. Italiano, P. Lecine, R. A. Shivdasani, and J. H. Hartwig, “Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes,” J. Cell Biol. 147(6), 1299–1312 (1999).
[Crossref] [PubMed]

Hayden, R. S.

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[Crossref] [PubMed]

Hirata, S.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Holyoake, T. L.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Italiano, J. E.

J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
[Crossref] [PubMed]

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
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K. R. Machlus and J. E. Italiano., “The incredible journey: From megakaryocyte development to platelet formation,” J. Cell Biol. 201(6), 785–796 (2013).
[Crossref] [PubMed]

J. E. Italiano, P. Lecine, R. A. Shivdasani, and J. H. Hartwig, “Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes,” J. Cell Biol. 147(6), 1299–1312 (1999).
[Crossref] [PubMed]

Iurlo, A.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Jameson, D. M.

D. M. Jameson, V. Thomas, and D. M. Zhou, “Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase,” Biochim. Biophys. Acta 994(2), 187–190 (1989).
[Crossref] [PubMed]

Johnson, M. L.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

Jones, G. E.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Kaplan, D.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

Kaplan, D. L.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[Crossref] [PubMed]

I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
[Crossref] [PubMed]

Karaliota, S.

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

Karalis, K. P.

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

Karlsson, S. M.

J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
[Crossref] [PubMed]

Kaushansky, K.

K. Kaushansky, “The molecular mechanisms that control thrombopoiesis,” J. Clin. Invest. 115(12), 3339–3347 (2005).
[Crossref] [PubMed]

Kelly, K. M.

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

Koike, T.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Laghi, L.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Lakowicz, J. R.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

Lecine, P.

J. E. Italiano, P. Lecine, R. A. Shivdasani, and J. H. Hartwig, “Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes,” J. Cell Biol. 147(6), 1299–1312 (1999).
[Crossref] [PubMed]

Lee, K.

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[Crossref] [PubMed]

Leon, C.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Levine, R. F.

N. Williams and R. F. Levine, “The origin, development and regulation of megakaryocytes,” Br. J. Haematol. 52(2), 173–180 (1982).
[Crossref] [PubMed]

Levine, R. L.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Liaudanskaya, V.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

Liu, Z.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

Liuzzi, G. M.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Lova, P.

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Lovett, M.

I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
[Crossref] [PubMed]

Machesky, L. M.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Machlus, K. R.

K. R. Machlus and J. E. Italiano., “The incredible journey: From megakaryocyte development to platelet formation,” J. Cell Biol. 201(6), 785–796 (2013).
[Crossref] [PubMed]

Malara, A.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Mazutis, L.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

McLaughlin-Drubin, M. E.

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Medvetz, D. A.

J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
[Crossref] [PubMed]

Miccolis, A.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Michie, A. M.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Monypenny, J.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Moratti, R.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Münger, K.

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Nakamura, S.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Nakauchi, H.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Nishimura, S.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Nowaczyk, K.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

Ochi, K.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Okita, K.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Pallotta, I.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
[Crossref] [PubMed]

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Panebianco, C.

T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
[Crossref] [PubMed]

Pecci, A.

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Perotti, C.

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Pouli, D.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
[Crossref] [PubMed]

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Quinn, K. P.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[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]

Ramanujam, N.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Raspanti, M.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

Rebuzzini, P.

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Rice, W.

I. Pallotta, M. Lovett, W. Rice, D. L. Kaplan, and A. Balduini, “Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis,” PLoS One 4(12), e8359 (2009).
[Crossref] [PubMed]

Riching, K. M.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Rius-Diaz, F.

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

Rosti, V.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Ruddy, B.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Sawaguchi, A.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Schachtner, H.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Seo, H.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Shi, Z. D.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
[Crossref] [PubMed]

Shivdasani, R. A.

J. E. Italiano, P. Lecine, R. A. Shivdasani, and J. H. Hartwig, “Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes,” J. Cell Biol. 147(6), 1299–1312 (1999).
[Crossref] [PubMed]

Sinclair, A.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Skala, M. C.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Sola-Visner, M.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

Sood, D.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

Spedden, E.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

Sridharan, G.

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Sridharan, G. V.

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
[Crossref] [PubMed]

Staii, C.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

Stringari, C.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Stuntz, E.

E. Stuntz, Y. Gong, D. Sood, V. Liaudanskaya, D. Pouli, K. P. Quinn, C. Alonzo, Z. Liu, D. L. Kaplan, and I. Georgakoudi, “Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity,” Sci. Rep. 7(1), 1041 (2017).
[Crossref] [PubMed]

Szmacinski, H.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

Takahashi, N.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Takayama, N.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Tenni, R.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

Thomas, S. G.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Thomas, V.

D. M. Jameson, V. Thomas, and D. M. Zhou, “Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase,” Biochim. Biophys. Acta 994(2), 187–190 (1989).
[Crossref] [PubMed]

Thon, J. N.

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
[Crossref] [PubMed]

Thrasher, A. J.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Tira, M. E.

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Torti, M.

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Tromberg, B. J.

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
[Crossref] [PubMed]

Varone, A.

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Vercellino, M.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

Viarengo, G.

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
[Crossref] [PubMed]

Visai, L.

V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Vukovic, M.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

Ware, J.

A. T. Franco, A. Corken, and J. Ware, “Platelets at the interface of thrombosis, inflammation, and cancer,” Blood 126(5), 582–588 (2015).
[Crossref] [PubMed]

Watanabe, A.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

Watson, S. P.

H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

White, J. G.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

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N. Williams and R. F. Levine, “The origin, development and regulation of megakaryocytes,” Br. J. Haematol. 52(2), 173–180 (1982).
[Crossref] [PubMed]

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M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

Xylas, J.

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Yamanaka, S.

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
[Crossref] [PubMed]

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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]

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D. M. Jameson, V. Thomas, and D. M. Zhou, “Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase,” Biochim. Biophys. Acta 994(2), 187–190 (1989).
[Crossref] [PubMed]

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).
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Biochemistry (1)

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by complex I binding,” Biochemistry 47(36), 9636–9645 (2008).
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Biochim. Biophys. Acta (1)

D. M. Jameson, V. Thomas, and D. M. Zhou, “Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase,” Biochim. Biophys. Acta 994(2), 187–190 (1989).
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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).
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H. Schachtner, S. D. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, and L. M. Machesky, “Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane,” Blood 121(13), 2542–2552 (2013).
[Crossref] [PubMed]

A. Malara, C. Gruppi, I. Pallotta, E. Spedden, R. Tenni, M. Raspanti, D. Kaplan, M. E. Tira, C. Staii, and A. Balduini, “Extracellular matrix structure and nano-mechanics determine megakaryocyte function,” Blood 118(16), 4449–4453 (2011).
[Crossref] [PubMed]

M. Bender, J. N. Thon, A. J. Ehrlicher, S. Wu, L. Mazutis, E. Deschmann, M. Sola-Visner, J. E. Italiano, and J. H. Hartwig, “Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein,” Blood 125(5), 860–868 (2015).
[Crossref] [PubMed]

A. T. Franco, A. Corken, and J. Ware, “Platelets at the interface of thrombosis, inflammation, and cancer,” Blood 126(5), 582–588 (2015).
[Crossref] [PubMed]

A. Malara, C. Gruppi, P. Rebuzzini, L. Visai, C. Perotti, R. Moratti, C. Balduini, M. E. Tira, and A. Balduini, “Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A,” Blood 117(8), 2476–2483 (2011).
[Crossref] [PubMed]

Br. J. Haematol. (1)

N. Williams and R. F. Levine, “The origin, development and regulation of megakaryocytes,” Br. J. Haematol. 52(2), 173–180 (1982).
[Crossref] [PubMed]

Cancer Res. (1)

A. Varone, J. Xylas, K. P. Quinn, D. Pouli, G. Sridharan, M. E. McLaughlin-Drubin, C. Alonzo, K. Lee, K. Münger, and I. Georgakoudi, “Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues,” Cancer Res. 74(11), 3067–3075 (2014).
[Crossref] [PubMed]

Cell Stem Cell (1)

S. Nakamura, N. Takayama, S. Hirata, H. Seo, H. Endo, K. Ochi, K. Fujita, T. Koike, K. Harimoto, T. Dohda, A. Watanabe, K. Okita, N. Takahashi, A. Sawaguchi, S. Yamanaka, H. Nakauchi, S. Nishimura, and K. Eto, “Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells,” Cell Stem Cell 14(4), 535–548 (2014).
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Chem. Rev. (1)

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T. A. Giancaspero, G. Busco, C. Panebianco, C. Carmone, A. Miccolis, G. M. Liuzzi, M. Colella, and M. Barile, “FAD synthesis and degradation in the nucleus create a local flavin cofactor pool,” J. Biol. Chem. 288(40), 29069–29080 (2013).
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K. R. Machlus and J. E. Italiano., “The incredible journey: From megakaryocyte development to platelet formation,” J. Cell Biol. 201(6), 785–796 (2013).
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K. Kaushansky, “The molecular mechanisms that control thrombopoiesis,” J. Clin. Invest. 115(12), 3339–3347 (2005).
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J. N. Thon, D. A. Medvetz, S. M. Karlsson, and J. E. Italiano., “Road blocks in making platelets for transfusion,” J. Thromb. Haemost. 13(Suppl 1), S55–S62 (2015).
[Crossref] [PubMed]

A. Balduini, I. Pallotta, A. Malara, P. Lova, A. Pecci, G. Viarengo, C. L. Balduini, and M. Torti, “Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes,” J. Thromb. Haemost. 6(11), 1900–1907 (2008).
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PLoS One (1)

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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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Sci. Rep. (3)

K. P. Quinn, G. V. Sridharan, R. S. Hayden, D. L. Kaplan, K. Lee, and I. Georgakoudi, “Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation,” Sci. Rep. 3(1), 3432 (2013).
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C. A. Alonzo, S. Karaliota, D. Pouli, Z. Liu, K. P. Karalis, and I. Georgakoudi, “Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function,” Sci. Rep. 6(1), 31012 (2016).
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Sci. Transl. Med. (1)

D. Pouli, M. Balu, C. A. Alonzo, Z. Liu, K. P. Quinn, F. Rius-Diaz, R. M. Harris, K. M. Kelly, B. J. Tromberg, and I. Georgakoudi, “Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis,” Sci. Transl. Med. 8(367), 367ra169 (2016).
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V. Abbonante, C. A. Di Buduo, C. Gruppi, A. Malara, U. Gianelli, G. Celesti, A. Anselmo, L. Laghi, M. Vercellino, L. Visai, A. Iurlo, R. Moratti, G. Barosi, V. Rosti, and A. Balduini, “Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis,” Stem Cells 34(4), 1123–1133 (2016).
[Crossref] [PubMed]

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Figures (8)

Fig. 1
Fig. 1 Morphological stages of megakaryocytic development and platelet generation. A. Schematic of morphological stages of megakaryocytic development, indicating the nuclear configurations and cytoplasmic transformations. Cell examples for each stage are also shown enlarged as redox ratio images. Scale bar is 15 µm. B. Representative transmission images displaying typical cellular diversity within image fields and C. Corresponding redox ratio maps. Examples of cells in several differentiation stages are noted (II-VI). Black arrows in B point to cytoplasmic extensions from MKs during terminal differentiation. The advantage of TPEF images in non-invasively distinguishing nuclear morphology and localization is evident. Scale bar is 20µm for all images.
Fig. 2
Fig. 2 Morphological evaluation of megakaryocytic development. A-C. MK population analysis, quantifying the proportional contribution of each differentiation stage before (Day 0) and after (Day1) fibronectin adhesion as well as overall contributions. The raw cell numbers and corresponding percentages are shown as polar area diagrams with the area of a sector representing each stage’s contribution. D. Automated quantification of nuclear to cytoplasmic ratio. * denotes p<0.05 with statistical significance calculated by ANOVA and post-hoc Tukey test.
Fig. 3
Fig. 3 NAD(P)H fluorescence lifetime phasor analysis during megakaryocytic differentiation. A-E Phasor maps compiled for each differentiation stage, pseudocolored based on phasor point density (brighter color hues indicate higher spatial density). Dashed lines depict linear fits to the phasor distributions, with respective distribution centroids indicated by black circles. Image inserts show representative cells from each stage, pseudocolored based on bound NAD(P)H fraction maps. Scale bars are 15um for all images. F. Centroid linear trajectory comparison for all groups.
Fig. 4
Fig. 4 Cell based functional quantification. A. Mean Redox Ratio and B. Mean Bound Fraction calculation from MKs in every differentiating stage averaged among all cells belonging in each stage. Means and standard errors presented, * denotes p<0.05 with statistical significance calculated by ANOVA and post-hoc Tukey test. C. Cell based RR and BF histograms. Histogram inserts show component weights based on the extracted fit parameters from all cells examined (Appendix Fig. 8). Reversed colored representative images are also presented with pixels colored based on which distribution component they belong to for each respective biomarker.
Fig. 5
Fig. 5 Mitochondria support MK differentiation. 2P NAD(P)H autofluorescence and confocal mitotracker orange images from MKs at various stages of differentiation.
Fig. 6
Fig. 6 Image analysis steps. A. Overlay of the co-registered NAD(P)H (green) and FAD (red) channels, B. Cellular tracing and classification overlaid on RR respective map C. Automated segmentation of the selected cells after removal of background and saturated pixels. Both the overall cellular masks incorporating nuclei (magenta & white pixels) and the stricter intracellular feature masks (white pixels only) are shown. Scale bar is 20 µm for all images.
Fig. 7
Fig. 7 Flowchart displaying the decision-making steps utilized for the assignment of the MK differentiation classes. Small cells belonging to categories III and IV were very sparsely observed in our cultures (<5%). In those instances, as nuclear morphology and N:C ratio combinations are different between these classes and class II, misclassification is usually avoided.
Fig. 8
Fig. 8 A-B. Cell based RR and BF histograms from all cells examined. Box plots with outliers as dark dots outside the whiskers are shown. C-D. Cell based RR and BF binormal fitted histograms from all cells examined after outlier exclusion. The respective extracted 2-component normal mixture parameters are shown below each distribution.

Tables (1)

Tables Icon

Table 1 Morphometric analysis

Metrics