Module 8: Molecular Control of de novo Haemopoietic Stem Cell Generation

 Module Leader Professor Doug Hilton
 Host Organisation Walter and Eliza Hall Institute

Module description

The use of haemopoietic stem cells (HSCs) represents one of only a few examples of the successful application of stem cells to regenerative medicine; however, their paucity limits their more extensive use. In principle, two approaches might be pursued to generate larger number of HSCs: the expansion of pre-existing HSCs from donors or the de novo formation of HSCs from a more abundant source - e.g. pluripotent cell lines. The later option is likely to prove most amenable to clinical success since the advent of induced pluripotency technology, which will enable the derivation of patient specific induced pluripotent stem (iPS) cells.

If we could understand the molecular events that allow de novo HSC generation, then this knowledge might be applied to efficiently direct formation of HSCs from conventional ES cells or iPS cells. This approach has not been feasible to date because, until recently, the precise cellular mechanisms of adult HSC formation in the aorta-gonad-mesonephros (AGM) have remained elusive. The breakthrough has come from studies by Dr Samir Taoudi who developed a compaction-reaggregation technique, which, when coupled with a novel growth factor combination, permits efficient de novo HSC formation in culture – mirroring the process that occurs in the embryo. Using this system he discovered that the rapid generation of the adult HSC pool arise from the maturation of pre-HSCs, which are spatially restricted to intra-aortic clusters within the dorsal aorta, to an adult HSC fate.

Aims

  1. Determine whether mouse mutants that display adult stem cell phenotypes have changes in their ability to produce HSCs de novo.
  2. Define the transcriptional changes that occur during the pre-HSC to definitive HSC transition.
  3. Identify functionally important genes for definitive HSC induction.

Module Leader biography

Professor Doug Hilton undertook his PhD at WEHI, working with Professors Don Metcalf and Nick Nicola, to purify and patent the LIF protein.

Professor Hilton went on to complete a post-doc at the Whitehead Institute at MIT on how red blood cell surface receptors recognise erythropoietin, and upon returning to WEHI discovered the suppressors of cytokine signalling (SOCS) protein family. He has recently been using large-scale genomics to track down the genes that regulate blood cell formation. Professor Hilton is the Director of the Walter and Eliza Hall Institute and head of the Division of Molecular Medicine.

Contact details

 E-mail  hilton@wehi.edu.au
 Phone   +61 3 9345 2621
 Web  www.wehi.edu.au

Selected publications

  1. HILTON, D.J., Nicola, N.A. and Metcalf, D. Purification of a murine leukemia inhibitory factor from Krebs Ascites cells. Anal. Biochem. 173: 359-367, 1988 [110 Citations]
  2. Williams, R.L., HILTON, D.J., Pease, S., Willson, T.A., Stewart, C.L., Gearing, D.P., Wagner, E.F., Metcalf, D.,Nicola, N.A. and Gough, N.M. Myeloid leukemia inhibitory factor (LIF) maintains the developmental potential of embryonic stem cells. Nature 336: 684-687, 1988 [856 Citations]
  3. HILTON, D.J., Hilton, A.A., Raicevic, A., Rakar, S., Harrison-Smith, M., Gough, N.M., Begley, C.G., Metcalf, D.,Nicola, N.A. and Willson, T.A. Cloning of a murine IL-11 receptor alpha chain; requirement of gp130 for high affinity binding and signal transduction. EMBO J. 13: 4765-75, 1994 [209 Citations]
  4. HILTON, D.J., Zhang, J-G., Metcalf, D., Alexander, W., Nicola, N.A. and Willson, T.A. Cloning and characterisation of a novel shared component of the interleukin-4 and interleukin-13 receptors. Proc. Natl. Acad. Sci. USA 93: 497-501, 1996 [268 Citations]
  5. Starr, R., Willson, T.A., Viney, E.M., Murray, L.J.L., Rayner, J.R., Jenkins, B.J., Gonda, T.J., Alexander, W.S., Metcalf, D., Nicola, N.A. and HILTON, D.J. A family of cytokine-inducible inhibitors of signal transduction. Nature 387: 917-921, 1997 [1052 Citations]
  6. HILTON, D.J., Richardson, R.T., Alexander, W.S., Viney, E.M., Willson, T.A., Sprigg, N.S., Starr, R., Nicholson, S.E., Metcalf, D. and Nicola, N.A. Twenty proteins containing a c-terminal SOCS box comprise five structural classes. Proc. Natl. Acad. Sci. USA 95: 114-119, 1998 [310 Citations]
  7. Alexander, W.S., Starr, R., Fenner, J.E., Scott, C.L., Handman, E., Sprigg, N.S., Corbin, J.E., Cornish, A.L., Darwiche, R., Owczarek, C.M., Kay, T.W.H., Nicola, N.A., Hertzog, P.J., Metcalf, D. and HILTON, D.J. SOCS1 is a critical regulator of interferon gamma signalling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98: 597-608, 1999 [344 Citations]
  8. Metcalf, D., Greenhalgh, C.J., Viney, E., Willson, T., Nicola, N.A., HILTON, D.J., and Alexander, W.S. Gigantism in mice lacking suppressor of cytokine signaling-2. Nature 405:1069-1073, 2000 [204 Citations]
  9. Carpinelli MR*, HILTON DJ*, Metcalf D, Antonchuk JL, Hyland CD, Mifsud SL, Di Rago L, Hilton AA, Willson TA, Roberts AW, Ramsay RG, Nicola NA, Alexander WS. Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc Natl Acad Sci U S A. 101(17):6553-8, 2004. (* joint first authors) [58 Citations]
  10. Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA, Henley KJ, Ellis S, Voss AK, Metcalf D, HILTON DJ*, Alexander WS*, Kile BT* The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells Nat. Immunol. 9:810-9, 2008 (* joint senior authors) [4 Citations]