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Leukemia Inhibitory Factor Increases Survival of Pluripotent Stem Cell-Derived Cardiomyocytes

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A Correction to this article was published on 14 November 2017

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Abstract

Leukemia inhibitory factor (LIF) is a growth factor with pleiotropic biological functions. It has been reported that LIF acts at different stages during mesoderm development. Also, it has been shown that LIF has a cytoprotective effect on neonatal murine cardiomyocytes (CMs) in culture, but little is known about the role of LIF during human cardiogenesis. Thus, we analyzed the effects of LIF on human pluripotent stem cells (PSC) undergoing cardiac differentiation. We first showed that LIF is expressed in the human heart during early development. We found that the addition of LIF within a precise time window during the in vitro differentiation process significantly increased CMs viability. This finding was associated to a decrease in the expression of pro-apoptotic protein Bax, which coincides with a reduction of the apoptotic rate. Therefore, the addition of LIF may represent a promising strategy for increasing CMs survival derived from PSCs.

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  • 14 November 2017

    Please note that Carolina Blüguermann’s surname was misspelled (as Blugüermann) in this article as originally published.

References

  1. Taupin, J.L., Pitard, V., Dechanet, J., Miossec, V., Gualde, N., & Moreau, J.F. (1998). Leukemia inhibitory factor: part of a large ingathering family. International Reviews of Immunology, 16(3–4), 397–426.

    Article  CAS  PubMed  Google Scholar 

  2. Rathjen, P.D., Toth, S., Willis, A., Heath, J.K., & Smith, A.G. (1990). Differentiation inhibiting activity is produced in matrix-associated and diffusible forms that are generated by alternate promoter usage. Cell, 62(6), 1105–1114.

    Article  CAS  PubMed  Google Scholar 

  3. Godard, A., Heymann, D., Raher, S., Anegon, I., Peyrat, M.A., Le Mauff, B., et al. (1992). High and low affinity receptors for human interleukin for DA cells/leukemia inhibitory factor on human cells. Molecular characterization and cellular distribution. The Journal of Biological Chemistry, 267(5), 3214–3222.

    CAS  PubMed  Google Scholar 

  4. Fischer, P., & Hilfiker-Kleiner, D. (2008). Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects. British Journal of Pharmacology, 153 Suppl 1, S414–S427.

    CAS  PubMed  Google Scholar 

  5. Yoshida, K., Taga, T., Saito, M., Suematsu, S., Kumanogoh, A., Tanaka, T., et al. (1996). Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proceedings of the National Academy of Sciences of the United States of America, 93 (1), 407–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sheng, Z., Pennica, D., Wood, W.I., & Chien, K.R. (1996). Cardiotrophin-1 displays early expression in the murine heart tube and promotes cardiac myocyte survival. Development, 122(2), 419–428.

    CAS  PubMed  Google Scholar 

  7. Conquet, F., Peyriéras, N, Tiret, L., & Brûlet, P. (1992). Inhibited gastrulation in mouse embryos overexpressing the leukemia inhibitory factor. Proceedings of the National Academy of Sciences of the United States of America, 89(17), 8195–8199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fujio, Y., Kunisada, K., Hirota, H., Yamauchi-Takihara, K., & Kishimoto, T. (1997). Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. The Journal of Clinical Investigation, 99(12), 2898–2905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kunisada, K., Tone, E., Fujio, Y., Matsui, H., Yamauchi-Takihara, K., & Kishimoto, T. (1998). Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation, 98(4), 346–352.

    Article  CAS  PubMed  Google Scholar 

  10. Nelson, S.K., Wong, G.H., & McCord, J.M. (1995). Leukemia inhibitory factor and tumor necrosis factor induce manganese superoxide dismutase and protect rabbit hearts from reperfusion injury. Journal of Molecular and Cellular Cardiology, 27(1), 223–229.

    Article  CAS  PubMed  Google Scholar 

  11. Yang, X., Cohen, M.V., & Downey, J.M. (2010). Mechanism of cardioprotection by early ischemic preconditioning. Cardiovascular Drugs and Therapy, 24(3), 225–234.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Van Vliet, P., Wu, S.M., Zaffran, S., & Pucéat, M. (2012). Early cardiac development: a view from stem cells to embryos. Cardiovascular Research, 96(3), 352–362.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Poon, E., Kong, C.W., & Li, R.A. (2011). Human pluripotent stem cell-based approaches for myocardial repair: from the electrophysiological perspective. Molecular Pharmaceutics, 8(5), 1495–1504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zou, Y., Takano, H., Mizukami, M., Akazawa, H., Qin, Y., Toko, H., et al. (2003). Leukemia inhibitory factor enhances survival of cardiomyocytes and induces regeneration of myocardium after myocardial infarction. Circulation, 108(6), 748–753.

    Article  CAS  PubMed  Google Scholar 

  15. Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.

    Article  CAS  PubMed  Google Scholar 

  16. Romorini, L., Scassa, M.E., Videla Richardson, G., Blüguermann, C, Jaquenod de Giusti, C., Questa, M., et al. (2012). Activation of apoptotic signalling events in human embryonic stem cells upon Coxsackievirus B3 infection. Apoptosis, 17(2), 132–142.

    Article  PubMed  Google Scholar 

  17. Scassa, M.E., Jaquenod de Giusti, C., Questa, M., Pretre, G., Richardson, G.A.V., Bluguermann, C., et al. (2011). Human embryonic stem cells and derived contractile embryoid bodies are susceptible to Coxsakievirus B infection and respond to interferon Ibeta treatment. Stem Cell Research, 6(1), 13–22.

    Article  CAS  PubMed  Google Scholar 

  18. García, C.P., Videla Richardson, G.A., Romorini, L., Miriuka, S.G., Sevlever, G.E., & Scassa, M.E. (2014). Topoisomerase I inhibitor, camptothecin, induces apoptogenic signaling in human embryonic stem cells. Stem Cell Research, 12(2), 400–414.

    Article  PubMed  Google Scholar 

  19. Wu, L., Bluguermann, C., Kyupelyan, L., Latour, B., Gonzalez, S., Shah, S., et al. (2013). Human developmental chondrogenesis as a basis for engineering chondrocytes from pluripotent stem cells. Stem Cell Reports, 1(6), 575–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Willems, E., Spiering, S., Davidovics, H., Lanier, M., Xia, Z., Dawson, M., et al. (2011). Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm. Circulation Research, 109(4), 360–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang, L., Soonpaa, M.H., Adler, E.D., Roepke, T.K., Kattman, S.J., Kennedy, M., et al. (2008). Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature, 453 (7194), 524–528.

    Article  CAS  PubMed  Google Scholar 

  22. Vallier, L., Touboul, T., Chng, Z., Brimpari, M., Hannan, N., Millan, E., et al. (2009). Early cell fate decisions of human embryonic stem cells and mouse epiblast stem cells are controlled by the same signalling pathways. PLoS One, 4(6), e6082.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lanier, M., Schade, D., Willems, E., Tsuda, M., Spiering, S., Kalisiak, J., et al. (2012). Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: a structure-activity relationship study based on inhibitors for the Wnt response. Journal of Medicinal Chemistry, 55(2), 697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bader, A., Gruss, A., Höllrigl, A, Al-Dubai, H., Capetanaki, Y., & Weitzer, G. (2001). Paracrine promotion of cardiomyogenesis in embryoid bodies by LIF modulated endoderm. Differentiation, 68(1), 31–43.

    Article  CAS  PubMed  Google Scholar 

  25. Lough, J., & Sugi, Y. (2000). Endoderm and heart development. Developmental Dynamics, 217(4), 327–342.

    Article  CAS  PubMed  Google Scholar 

  26. Wong, W.W.L., & Puthalakath, H. (2008). Bcl-2 family proteins: the sentinels of the mitochondrial apoptosis pathway. IUBMB Life, 60(6), 390–397.

    Article  CAS  PubMed  Google Scholar 

  27. Hirota, H., Chen, J., Betz, U.A., Rajewsky, K., Gu, Y., Ross, J Jr, et al. (1999). Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell, 97(2), 189–198.

    Article  CAS  PubMed  Google Scholar 

  28. Schust, J., Sperl, B., Hollis, A., Mayer, T.U., & Berg, T. (2006). Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chemistry & Biology, 13(11), 1235–1242.

    Article  CAS  Google Scholar 

  29. Passier, R., Denning, C., & Mummery, C. (2006). Cardiomyocytes from human embryonic stem cells. Handbook of Experimental Pharmacology, 174, 101–122.

    CAS  Google Scholar 

  30. Bader, A., Al-Dubai, H., & Weitzer, G. (2000). Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circulation Research, 86(7), 787–794.

    Article  CAS  PubMed  Google Scholar 

  31. Grosset, C., Jazwiec, B., Taupin, J.L., Liu, H., Richard, S., Mahon, F.X., et al. (1995). In vitro biosynthesis of leukemia inhibitory factor/human interleukin for DA cells by human endothelial cells: differential regulation by interleukin-1 alpha and glucocorticoids. Blood, 86(10), 3763–3770.

    CAS  PubMed  Google Scholar 

  32. Liu, X., Tseng, S.C.G., Zhang, M.C., Chen, S.Y., Tighe, S., Lu, W.J., et al. (2015). LIF-JAK1-STAT3 Signaling delays contact inhibition of human corneal endothelial cells. Cell Cycle, 14(8), 1197–1206.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dahéron, L, Opitz, S.L., Zaehres, H., Lensch, M.W., Lensch, W.M., Andrews, P.W., et al. (2004). LIF/STAT3 Signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells, 22(5), 770–778.

    Article  PubMed  Google Scholar 

  34. Aghajanova, L., Skottman, H., Strömberg, A M, Inzunza, J., Lahesmaa, R., & Hovatta, O. (2006). Expression of leukemia inhibitory factor and its receptors is increased during differentiation of human embryonic stem cells. Fertility and Sterility, 86(4 Suppl), 1193–209.

    Article  CAS  PubMed  Google Scholar 

  35. Skottman, H., Strömberg, A.M., Matilainen, E., Inzunza, J., Hovatta, O., & Lahesmaa, R. (2006). Unique gene expression signature by human embryonic stem cells cultured under serum-free conditions correlates with their enhanced and prolonged growth in an undifferentiated stage. Stem Cells, 24(1), 151– 167.

    Article  CAS  PubMed  Google Scholar 

  36. Motoyama, N., Wang, F., Roth, K.A., Sawa, H., Nakayama, K., Nakayama, K., et al. (1995). Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science, 267(5203), 1506–1510.

    Article  CAS  PubMed  Google Scholar 

  37. Durbin, J.E., Hackenmiller, R., Simon, M.C., & Levy, D.E. (1996). Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell, 84(3), 443–450.

    Article  CAS  PubMed  Google Scholar 

  38. Meraz, M.A., White, J.M., Sheehan, K.C., Bach, E.A., Rodig, S.J., Dighe, A.S., et al. (1996). Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell, 84(3), 431–442.

    Article  CAS  PubMed  Google Scholar 

  39. Wang, F., Trial, J., Diwan, A., Gao, F., Birdsall, H., Entman, M., et al. (2002). Regulation of cardiac fibroblast cellular function by leukemia inhibitory factor. Journal of Molecular and Cellular Cardiology, 34 (10), 1309–1316.

    Article  CAS  PubMed  Google Scholar 

  40. Nakajima, S., Tanaka, T., Umesaki, N., & Ishiko, O. (2003). Leukemia inhibitory factor regulates cell survival of normal human endometrial stromal cells. International Journal of Molecular Medicine, 11(3), 353–356.

    CAS  PubMed  Google Scholar 

  41. Cullinan, E.B., Abbondanzo, S.J., Anderson, P.S., Pollard, J.W., Lessey, B.A., & Stewart, C.L. (1996). Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proceedings of the National Academy of Sciences of the United States of America, 93(7), 3115–3120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Special thanks to Dario Fernandez Espinosa for his technical support.

Funding

This study was funded by Fondo para la Investigación Científica y Tecnológica (FONCyT) (PICT-2011-2717).

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Correspondence to Santiago Gabriel Miriuka.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Associate Editor Saptarsi Haldar oversaw the review of this article

Please note that Carolina Blüguermann’s surname was misspelled (as Blugüermann) in this article as originally published.

A correction to this article is available online at https://doi.org/10.1007/s12265-017-9771-z.

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Blüguermann, C., Romorini, L., Evseenko, D. et al. Leukemia Inhibitory Factor Increases Survival of Pluripotent Stem Cell-Derived Cardiomyocytes. J. of Cardiovasc. Trans. Res. 11, 1–13 (2018). https://doi.org/10.1007/s12265-017-9769-6

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  • DOI: https://doi.org/10.1007/s12265-017-9769-6

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