Skip to main content

Advertisement

SpringerLink
Log in

Developmental Stage-Dependent Effects of Leukemia Inhibitory Factor on Adipocyte Differentiation of Murine Bone Marrow Stromal Cells

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Studies describing the effects of leukemia inhibitory factor (LIF) on adipocyte differentiation in murine cells have shown varying results. For example, LIF has been reported to have a suppressive effect on adipocyte differentiation in the 3T3-L1 cell line, whereas it promoted adipocyte differentiation in the Ob1771 and 3T3-F442A cell lines. Thus, it is possible that the effects of LIF on adipogenesis vary with the developmental stage of the cells or tissues, but the details remain unclear. To further elucidate the role of LIF in adipogenesis, we investigated the effects of LIF on murine bone marrow stromal cells at the early and late stages of adipogenesis. LIF decreased the number of lipid foci and suppressed the expression levels of adipocyte differentiation markers at day 5; however, it enhanced these same traits at day 15. A previous report showed that the expression levels of Wnt signaling molecules are different at the early and late differentiation stages; therefore, we investigated the relationship between LIF and Wnt signaling. LIF affected the mRNA expression levels of different Wnt signaling molecules but inhibited the expression level of β-catenin protein at both days 5 and 15. Our data suggest that LIF has reciprocal roles during the early and late stages of adipocyte differentiation, regulating the Wnt signaling pathway.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Prockop, D. J. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276, 71–74.

    Article  CAS  PubMed  Google Scholar 

  2. Friedenstein, A. J., Gorskaja, J. F., & Kulagina, N. N. (1976). Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Experimental Hematology, 4, 267–274.

    CAS  PubMed  Google Scholar 

  3. Owen, M. (1988). Marrow stromal stem cells. Journal of Cell Science Supplement, 10, 63–76.

    Article  CAS  PubMed  Google Scholar 

  4. Itoh, S., & Aubin, J. E. (2009). A novel purification method for multipotential skeletal stem cells. Journal of Cellular Biochemistry, 108, 368–377.

    Article  CAS  PubMed  Google Scholar 

  5. Caplan, A. I. (1991). Mesenchymal stem cells. Journal of Orthopaedic Research, 9, 641–650.

    Article  CAS  PubMed  Google Scholar 

  6. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.

    Article  CAS  PubMed  Google Scholar 

  7. Tang, Q. Q., & Lane, M. D. (2012). Adipogenesis: From stem cell to adipocyte. Annual Review of Biochemistry, 81, 715–736.

    Article  CAS  PubMed  Google Scholar 

  8. MacDougald, O. A., & Lane, M. D. (1995). Transcriptional regulation of gene expression during adipocyte differentiation. Annual Review of Biochemistry, 64, 345–373.

    Article  CAS  PubMed  Google Scholar 

  9. Mandrup, S., & Lane, M. D. (1997). Regulating adipogenesis. Journal of Biological Chemistry, 272, 5367–5370.

    Article  CAS  PubMed  Google Scholar 

  10. Otto, T. C., & Lane, M. D. (2005). Adipose development: From stem cell to adipocyte. Critical Reviews in Biochemistry and Molecular Biology, 40, 229–242.

    Article  CAS  PubMed  Google Scholar 

  11. Muruganandan, S., Roman, A. A., & Sinal, C. J. (2009). Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: Cross talk with the osteoblastogenic program. Cellular and Molecular Life Sciences, 66, 236–253.

    Article  CAS  PubMed  Google Scholar 

  12. Hong, J. H., & Yaffe, M. B. (2006). TAZ: A beta-catenin-like molecule that regulates mesenchymal stem cell differentiation. Cell Cycle, 5, 176–179.

    Article  CAS  PubMed  Google Scholar 

  13. Ross, S. E., Hemati, N., Longo, K. A., Bennett, C. N., Lucas, P. C., Erickson, R. L., & MacDougald, O. A. (2000). Inhibition of adipogenesis by Wnt signaling. Science, 289, 950–953.

    Article  CAS  PubMed  Google Scholar 

  14. Kang, S., Bennett, C. N., Gerin, I., Rapp, L. A., Hankenson, K. D., & Macdougald, O. A. (2007). Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. Journal of Biological Chemistry, 282, 14515–14524.

    Article  CAS  PubMed  Google Scholar 

  15. Christodoulides, C., Lagathu, C., Sethi, J. K., & Vidal-Puig, A. (2009). Adipogenesis and WNT signalling. Trends in Endocrinology and Metabolism, 20, 16–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bennett, C. N., Longo, K. A., Wright, W. S., Suva, L. J., Lane, T. F., Hankenson, K. D., & MacDougald, O. A. (2005). Regulation of osteoblastogenesis and bone mass by Wnt10b. Proceedings of the National Academy of Sciences of the USA, 102, 3324–3329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Moldes, M., Zuo, Y., Morrison, R. F., Silva, D., Park, B. H., Liu, J., & Farmer, S. R. (2003). Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochemical Journal, 376, 607–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qiu, W., Andersen, T. E., Bollerslev, J., Mandrup, S., Abdallah, B. M., & Kassem, M. (2007). Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. Journal of Bone and Mineral Research, 22, 1720–1731.

    Article  CAS  PubMed  Google Scholar 

  19. Rawadi, G., Vayssiere, B., Dunn, F., Baron, R., & Roman-Roman, S. (2003). BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. Journal of Bone and Mineral Research, 18, 1842–1853.

    Article  CAS  PubMed  Google Scholar 

  20. Boland, G. M., Perkins, G., Hall, D. J., & Tuan, R. S. (2004). Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. Journal of Cellular Biochemistry, 93, 1210–1230.

    Article  CAS  PubMed  Google Scholar 

  21. Cho, H. H., Kim, Y. J., Kim, S. J., Kim, J. H., Bae, Y. C., Ba, B., & Jung, J. S. (2006). Endogenous Wnt signaling promotes proliferation and suppresses osteogenic differentiation in human adipose derived stromal cells. Tissue Engineering, 12, 111–121.

    Article  CAS  PubMed  Google Scholar 

  22. Bowers, R. R., & Lane, M. D. (2008). Wnt signaling and adipocyte lineage commitment. Cell Cycle, 7, 1191–1196.

    Article  CAS  PubMed  Google Scholar 

  23. Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E, Jr, & Yancopoulos, G. D. (1995). Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science, 267, 1349–1353.

    Article  CAS  PubMed  Google Scholar 

  24. Stahl, N., Boulton, T. G., Farruggella, T., Ip, N. Y., Davis, S., Witthuhn, B. A., et al. (1994). Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science, 263, 92–95.

    Article  CAS  PubMed  Google Scholar 

  25. White, U. A., & Stephens, J. M. (2011). The gp130 receptor cytokine family: Regulators of adipocyte development and function. Current Pharmaceutical Design, 17, 340–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Heinrich, P. C., Behrmann, I., Haan, S., Hermanns, H. M., Muller-Newen, G., & Schaper, F. (2003). Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal, 374, 1–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kimber, S. J. (2005). Leukaemia inhibitory factor in implantation and uterine biology. Reproduction, 130, 131–145.

    Article  CAS  PubMed  Google Scholar 

  28. Alonzi, T., Middleton, G., Wyatt, S., Buchman, V., Betz, U. A., Muller, W., et al. (2001). Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons. Molecular and Cellular Neuroscience, 18, 270–282.

    Article  CAS  PubMed  Google Scholar 

  29. Itoh, S., Udagawa, N., Takahashi, N., Yoshitake, F., Narita, H., Ebisu, S., & Ishihara, K. (2006). A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation. Bone, 39, 505–512.

    Article  CAS  PubMed  Google Scholar 

  30. Yoshitake, F., Itoh, S., Narita, H., Ishihara, K., & Ebisu, S. (2008). Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. Journal of Biological Chemistry, 283, 11535–11540.

    Article  CAS  PubMed  Google Scholar 

  31. Williams, R. L., Hilton, D. J., Pease, S., Willson, T. A., Stewart, C. L., Gearing, D. P., et al. (1988). Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature, 336, 684–687.

    Article  CAS  PubMed  Google Scholar 

  32. Falconi, D., Oizumi, K., & Aubin, J. E. (2007). Leukemia inhibitory factor influences the fate choice of mesenchymal progenitor cells. Stem Cells, 25, 305–312.

    Article  CAS  PubMed  Google Scholar 

  33. Nuttall, M. E., & Gimble, J. M. (2004). Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications. Current Opinion in Pharmacology, 4, 290–294.

    Article  CAS  PubMed  Google Scholar 

  34. Beresford, J. N., Bennett, J. H., Devlin, C., Leboy, P. S., & Owen, M. E. (1992). Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. Journal of Cell Science, 102(Pt 2), 341–351.

    CAS  PubMed  Google Scholar 

  35. Aubert, J., Dessolin, S., Belmonte, N., Li, M., McKenzie, F. R., Staccini, L., et al. (1999). Leukemia inhibitory factor and its receptor promote adipocyte differentiation via the mitogen-activated protein kinase cascade. Journal of Biological Chemistry, 274, 24965–24972.

    Article  CAS  PubMed  Google Scholar 

  36. Mori, M., Yamaguchi, K., & Abe, K. (1989). Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia. Biochem Biophys Res Commun, 160, 1085–1092.

    Article  CAS  PubMed  Google Scholar 

  37. Greenberg, A. S., Nordan, R. P., McIntosh, J., Calvo, J. C., Scow, R. O., & Jablons, D. (1992). Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: A possible role for interleukin 6 in cancer cachexia. Cancer Research, 52, 4113–4116.

    CAS  PubMed  Google Scholar 

  38. Bennett, C. N., Ross, S. E., Longo, K. A., Bajnok, L., Hemati, N., Johnson, K. W., et al. (2002). Regulation of Wnt signaling during adipogenesis. Journal of Biological Chemistry, 277, 30998–31004.

    Article  CAS  PubMed  Google Scholar 

  39. Longo, K. A., Wright, W. S., Kang, S., Gerin, I., Chiang, S. H., Lucas, P. C., et al. (2004). Wnt10b inhibits development of white and brown adipose tissues. Journal of Biological Chemistry, 279, 35503–35509.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the members of the Aubin lab for discussion. This work was supported by Grants-in-Aid for Scientific Research (24689070 and 25670809) from the Japan Society for the Promotion of Science.

Author information

Author notes

    Authors and Affiliations

    1. Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan

      Shun Ikeda, Shousaku Itoh, Yumiko Yamamoto, Yukako Yamauchi, Kenta Matsushita, Haruna Naruse & Mikako Hayashi

    Authors
    1. Shun Ikeda
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Shousaku Itoh
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yumiko Yamamoto
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yukako Yamauchi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Kenta Matsushita
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Haruna Naruse
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Mikako Hayashi
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Shousaku Itoh.

    Additional information

    Shun Ikeda and Shousaku Itoh have contributed equally to this work.

    Electronic supplementary material

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Ikeda, S., Itoh, S., Yamamoto, Y. et al. Developmental Stage-Dependent Effects of Leukemia Inhibitory Factor on Adipocyte Differentiation of Murine Bone Marrow Stromal Cells. Cell Biochem Biophys 74, 11–17 (2016). https://doi.org/10.1007/s12013-015-0703-8

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12013-015-0703-8

    Keywords

    Search

    Navigation