Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

TRAF6 Distinctly Regulates Hematopoietic Stem and Progenitors at Different Periods of Development in Mice

  • Kim, Hyekang (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Lee, Seungwon (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Lee, Seung-Woo (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology)
  • Received : 2018.05.01
  • Accepted : 2018.06.19
  • Published : 2018.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is identified as a signaling adaptor protein that regulates bone metabolism, immunity, and the development of several tissues. Therefore, its functions are closely associated with multiple diseases. TRAF6 is also involved in the regulation of hematopoiesis under steady-state conditions, but the role of TRAF6 in modulating hematopoietic stem and progenitor cells (HSPCs) during the developmental stages remains unknown. Here, we report that the deletion of TRAF6 in hematopoietic lineage cells resulted in the upregulation of HSPCs in the fetal liver at the prenatal period. However, in the early postnatal period, deletion of TRAF6 drastically diminished HSPCs in the bone marrow (BM), with severe defects in BM development and extramedullary hematopoiesis in the spleen being identified. In the analysis of adult HSPCs in a BM reconstitution setting, TRAF6 played no significant role in HSPC homeostasis, albeit it affected the development of T cells. Taken together, our results suggest that the role of TRAF6 in regulating HSPCs is altered in a spatial and temporal manner during the developmental course of mice.

Keywords

References

  1. Armstrong, A.P., Tometsko, M.E., Glaccum, M., Sutherland, C.L., Cosman, D., and Dougall, W.C. (2002). A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J. Biol. Chem. 277, 44347-44356. https://doi.org/10.1074/jbc.M202009200
  2. Babovic, S., and Eaves, C.J. (2014). Hierarchical organization of fetal and adult hematopoietic stem cells. Exp. Cell Res. 329, 185-191. https://doi.org/10.1016/j.yexcr.2014.08.005
  3. Balmer, M.L., Schurch, C.M., Saito, Y., Geuking, M.B., Li, H., Cuenca, M., Kovtonyuk, L.V., McCoy, K.D., Hapfelmeier, S., Ochsenbein, A.F., et al. (2014). Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J. Immunol. 193, 5273-5283. https://doi.org/10.4049/jimmunol.1400762
  4. Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342. https://doi.org/10.1038/nature01658
  5. Bracken, A.P., and Helin, K. (2009). Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat. Rev. Cancer 9, 773-784. https://doi.org/10.1038/nrc2736
  6. Chou, S., and Lodish, H.F. (2010). Fetal liver hepatic progenitors are supportive stromal cells for hematopoietic stem cells. Proc. Natl. Acad. Sci. U S A 107, 7799-7804. https://doi.org/10.1073/pnas.1003586107
  7. Copley, M.R., Babovic, S., Benz, C., Knapp, D.J., Beer, P.A., Kent, D.G., Wohrer, S., Treloar, D.Q., Day, C., Rowe, K., et al. (2013). The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nat. Cell Biol. 15, 916-925. https://doi.org/10.1038/ncb2783
  8. Copley, M.R., and Eaves, C.J. (2013). Developmental changes in hematopoietic stem cell properties. Exp. Mol. Med. 45, e55. https://doi.org/10.1038/emm.2013.98
  9. Crane, G.M., Jeffery, E., and Morrison, S.J. (2017). Adult haematopoietic stem cell niches. Nat. Rev. Immunol. 17, 573-590. https://doi.org/10.1038/nri.2017.53
  10. Cumano, A., and Godin, I. (2007). Ontogeny of the hematopoietic system. Annu. Rev. Immunol. 25, 745-785. https://doi.org/10.1146/annurev.immunol.25.022106.141538
  11. Cumano, A., Dieterlen-Lievre, F., and Godin, I. (1996). Lymphoid potential, probed before circulation in mouse, is restricted to caudal intraembryonic splanchnopleura. Cell 86, 907-916. https://doi.org/10.1016/S0092-8674(00)80166-X
  12. Fang, J., Bolanos, L.C., Choi, K., Liu, X., Christie, S., Akunuru, S., Kumar, R., Wang, D., Chen, X., Greis, K.D., et al. (2017). Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat. Immunol. 18, 236-245.
  13. Fang, J., Muto, T., Kleppe, M., Bolanos, L.C., Hueneman, K.M., Walker, C.S., Sampson, L., Wellendorf, A.M., Chetal, K., Choi, K., et al. (2018). TRAF6 mediates basal activation of NF-kappaB necessary for hematopoietic stem cell homeostasis. Cell Rep. 22, 1250-1262. https://doi.org/10.1016/j.celrep.2018.01.013
  14. Gao, X., Xu, C., Asada, N., and Frenette, P.S. (2018). The hematopoietic stem cell niche: from embryo to adult. Development 145.
  15. Han, D., Walsh, M.C., Cejas, P.J., Dang, N.N., Kim, Y.F., Kim, J., Charrier-Hisamuddin, L., Chau, L., Zhang, Q., Bittinger, K., et al. (2013). Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity 38, 1211-1222. https://doi.org/10.1016/j.immuni.2013.05.012
  16. Harrison, D.E., Zhong, R.K., Jordan, C.T., Lemischka, I.R., and Astle, C.M. (1997). Relative to adult marrow, fetal liver repopulates nearly five times more effectively long-term than short-term. Exp. Hematol. 25, 293-297.
  17. He, S., Kim, I., Lim, M.S., and Morrison, S.J. (2011). Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors. Genes Dev. 25, 1613-1627. https://doi.org/10.1101/gad.2052911
  18. Hock, H., Hamblen, M.J., Rooke, H.M., Schindler, J.W., Saleque, S., Fujiwara, Y., and Orkin, S.H. (2004a). Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002-1007. https://doi.org/10.1038/nature02994
  19. Hock, H., Meade, E., Medeiros, S., Schindler, J.W., Valk, P.J., Fujiwara, Y., and Orkin, S.H. (2004b). Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev. 18, 2336-2341. https://doi.org/10.1101/gad.1239604
  20. Johns, J.L., and Christopher, M.M. (2012). Extramedullary hematopoiesis: a new look at the underlying stem cell niche, theories of development, and occurrence in animals. Vet. Pathol. 49, 508-523. https://doi.org/10.1177/0300985811432344
  21. Kamimae-Lanning, A.N., Krasnow, S.M., Goloviznina, N.A., Zhu, X., Roth-Carter, Q.R., Levasseur, P.R., Jeng, S., McWeeney, S.K., Kurre, P., and Marks, D.L. (2015). Maternal high-fat diet and obesity compromise fetal hematopoiesis. Mol. Metab. 4, 25-38. https://doi.org/10.1016/j.molmet.2014.11.001
  22. Khosravi, A., Yanez, A., Price, J.G., Chow, A., Merad, M., Goodridge, H.S., and Mazmanian, S.K. (2014). Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374-381. https://doi.org/10.1016/j.chom.2014.02.006
  23. Kim, I., He, S., Yilmaz, O.H., Kiel, M.J., and Morrison, S.J. (2006). Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. Blood 108, 737-744. https://doi.org/10.1182/blood-2005-10-4135
  24. Kim, I., Saunders, T.L., and Morrison, S.J. (2007). Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470-483. https://doi.org/10.1016/j.cell.2007.06.011
  25. Kollet, O., Dar, A., Shivtiel, S., Kalinkovich, A., Lapid, K., Sztainberg, Y., Tesio, M., Samstein, R.M., Goichberg, P., Spiegel, A., et al. (2006). Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12, 657-664. https://doi.org/10.1038/nm1417
  26. Kondo, M., Wagers, A.J., Manz, M.G., Prohaska, S.S., Scherer, D.C., Beilhack, G.F., Shizuru, J.A., and Weissman, I.L. (2003). Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu. Rev. Immunol. 21, 759-806. https://doi.org/10.1146/annurev.immunol.21.120601.141007
  27. Kwon, O., Lee, S., Kim, J.H., Kim, H., and Lee, S.W. (2015). Altered gut microbiota composition in Rag1-deficient mice contributes to modulating homeostasis of hematopoietic stem and progenitor cells. Immune Netw. 15, 252-259. https://doi.org/10.4110/in.2015.15.5.252
  28. Lamothe, B., Webster, W.K., Gopinathan, A., Besse, A., Campos, A.D., and Darnay, B.G. (2007). TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. Biochem. Biophys. Res. Commun. 359, 1044-1049. https://doi.org/10.1016/j.bbrc.2007.06.017
  29. Liu, Y., Yu, H., and Nimer, S.D. (2013). PI3K-Akt pathway regulates polycomb group protein and stem cell maintenance. Cell Cycle 12, 199-200. https://doi.org/10.4161/cc.23379
  30. Lomaga, M.A., Yeh, W.C., Sarosi, I., Duncan, G.S., Furlonger, C., Ho, A., Morony, S., Capparelli, C., Van, G., Kaufman, S., et al. (1999). TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13, 1015-1024. https://doi.org/10.1101/gad.13.8.1015
  31. Luo, Y., Chen, G.L., Hannemann, N., Ipseiz, N., Kronke, G., Bauerle, T., Munos, L., Wirtz, S., Schett, G., and Bozec, A. (2015). Microbiota from obese mice regulate Hematopoietic stem cell differentiation by altering the bone Niche. Cell Metab. 22, 886-894. https://doi.org/10.1016/j.cmet.2015.08.020
  32. Medvinsky, A., and Dzierzak, E. (1996). Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897-906. https://doi.org/10.1016/S0092-8674(00)80165-8
  33. Mikkola, H.K., and Orkin, S.H. (2006). The journey of developing hematopoietic stem cells. Development 133, 3733-3744. https://doi.org/10.1242/dev.02568
  34. Miyamoto, K., Yoshida, S., Kawasumi, M., Hashimoto, K., Kimura, T., Sato, Y., Kobayashi, T., Miyauchi, Y., Hoshi, H., Iwasaki, R., et al. (2011). Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J. Exp. Med. 208, 2175-2181. https://doi.org/10.1084/jem.20101890
  35. Morrison, S.J., and Scadden, D.T. (2014). The bone marrow niche for haematopoietic stem cells. Nature 505, 327-334. https://doi.org/10.1038/nature12984
  36. Morrison, S.J., Hemmati, H.D., Wandycz, A.M., and Weissman, I.L. (1995). The purification and characterization of fetal liver hematopoietic stem cells. Proc. Natl. Acad. Sci. U S A 92, 10302-10306. https://doi.org/10.1073/pnas.92.22.10302
  37. Muller, A.M., Medvinsky, A., Strouboulis, J., Grosveld, F., and Dzierzak, E. (1994). Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1, 291-301. https://doi.org/10.1016/1074-7613(94)90081-7
  38. Naito, A., Azuma, S., Tanaka, S., Miyazaki, T., Takaki, S., Takatsu, K., Nakao, K., Nakamura, K., Katsuki, M., Yamamoto, T., et al. (1999). Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4, 353-362. https://doi.org/10.1046/j.1365-2443.1999.00265.x
  39. Orkin, S.H., and Zon, L.I. (2008). Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631-644. https://doi.org/10.1016/j.cell.2008.01.025
  40. Park, I.K., Qian, D., Kiel, M., Becker, M.W., Pihalja, M., Weissman, I.L., Morrison, S.J., and Clarke, M.F. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302-305. https://doi.org/10.1038/nature01587
  41. Park, J.H., Lee, N.K., and Lee, S.Y. (2017). Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol. Cells 40, 706-713.
  42. Pietras, E.M., Warr, M.R., and Passegue, E. (2011). Cell cycle regulation in hematopoietic stem cells. J. Cell Biol. 195, 709-720. https://doi.org/10.1083/jcb.201102131
  43. Schuettpelz, L.G., and Link, D.C. (2013). Regulation of hematopoietic stem cell activity by inflammation. Front. Immunol. 4, 204.
  44. Walsh, M.C., Lee, J., and Choi, Y. (2015). Tumor necrosis factor receptor-associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol. Rev. 266, 72-92. https://doi.org/10.1111/imr.12302
  45. Weissman, I.L. (2000). Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157-168. https://doi.org/10.1016/S0092-8674(00)81692-X
  46. Winkler, I.G., Sims, N.A., Pettit, A.R., Barbier, V., Nowlan, B., Helwani, F., Poulton, I.J., van Rooijen, N., Alexander, K.A., Raggatt, L.J., et al. (2010). Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116, 4815-4828. https://doi.org/10.1182/blood-2009-11-253534
  47. Xie, P. (2013). TRAF molecules in cell signaling and in human diseases. J. Mol. Signal. 8, 7. https://doi.org/10.1186/1750-2187-8-7
  48. Yang, W.L., Wang, J., Chan, C.H., Lee, S.W., Campos, A.D., Lamothe, B., Hur, L., Grabiner, B.C., Lin, X., Darnay, B.G., et al. (2009). The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325, 1134-1138. https://doi.org/10.1126/science.1175065
  49. Ye, M., Zhang, H., Amabile, G., Yang, H., Staber, P.B., Zhang, P., Levantini, E., Alberich-Jorda, M., Zhang, J., Kawasaki, A., et al. (2013). C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nat. Cell Biol. 15, 385-394. https://doi.org/10.1038/ncb2698
  50. Yuan, J., Nguyen, C.K., Liu, X., Kanellopoulou, C., and Muljo, S.A. (2012). Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195-1200. https://doi.org/10.1126/science.1216557

Cited by

  1. Chronic immune response dysregulation in MDS pathogenesis vol.132, pp.15, 2018, https://doi.org/10.1182/blood-2018-03-784116
  2. Alleviation of Ultraviolet-B Radiation-Induced Photoaging by a TNFR Antagonistic Peptide, TNFR2-SKE vol.42, pp.2, 2019, https://doi.org/10.14348/molcells.2018.0423
  3. HIRA, a DiGeorge Syndrome Candidate Gene, Confers Proper Chromatin Accessibility on HSCs and Supports All Stages of Hematopoiesis vol.30, pp.7, 2020, https://doi.org/10.1016/j.celrep.2020.01.062