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Stem cell regulation

Billions of blood cells are produced in our body each day, due to highly controlled regulation of self-renewal and differentiation processes of blood stem cells. Blood cell production predominantly occurs in the bone marrow and the non-blood cell types present in the bone marrow (collectively called the bone marrow microenvironment) are important in helping to control blood cell production from stem cells. Incomplete production or function of the different blood cell types or problems arising in the function or composition of the non-blood cells that regulate blood cell production can lead to blood cell diseases such as cancers.

Research Overview

The Stem Cell Regulation Unit is interested in learning how stem cells, in particular blood cell-forming stem cells, are regulated to either increase in number (by a process termed self-renewal) or produce more blood cells (a process termed differentiation). We are also interested in learning how cells of the bone marrow microenvironment (where blood stem cells normally reside) interact with blood stem cells to regulate both self-renewal of blood stem cells and blood cell production from blood stem cells. We are passionate about translational research and collaborate with a number of clinicians in the Melbourne precinct.

Research Themes

The regulation of blood stem cell self-renewal and differentiation

Our research has pioneered the discovery that the different vitamin A receptors differentially regulate blood cell production. We have shown that vitamin A enhances blood stem cell self-renewal and that this requires one of the vitamin A receptors, retinoid acid receptor (RAR) gamma. We have also shown that the other receptor predominantly expressed by blood cells, RAR alpha, has the opposite effects on blood stem cells, enhancing their differentiation. Furthermore, we have developed two novel mouse models of the malignant blood cell disease, myelodysplastic syndromes, based on deregulated expression of the RAR gamma target gene, Hoxa1, and are currently using these models to determine how MDS occurs and find better therapies for this disease.

The roles of the bone marrow microenvironment in regulating blood cell production

Mature blood cells are predominantly produced from blood stem cells located in the bone marrow microenvironment. The roles of the non-blood cell types that comprise the bone marrow microenvironment in regulating blood cell production are not well-defined. We have previously shown that the vitamin A receptor, RAR gamma, is a key regulator of haematopoiesis via bone marrow microenvironment cells. Our studies are further exploring how RAR gamma deletion in different bone marrow microenvironment cells alters blood cell production.

Understanding how the cells of the bone marrow microenvironment respond to therapies used to treat cancers

Many drugs or irradiation procedures used to treat patients with a wide range of cancers cause severe and prolonged reductions in blood cell production, placing the patients at risk of bleeding or infection, which can be life-threatening. We have discovered that these cancer treatments not only affect the blood cells themselves, but also have major effects on the composition and function of the cells of the bone marrow microenvironment. We aim to improve recovery of the bone marrow microenvironment cells after cancer treatments, which in turn should aid in rapidly restoring blood cell production in these patients.

Determining changes in bone marrow microenvironments in blood cell cancers

Blood cell cancers can cause changes in the bone marrow microenvironment, which, in turn, can alter normal haematopoiesis and facilitate the progression of the blood cell cancers. We are using advanced imaging technologies to determine these changes in human bone marrow biopsies in studies that form part of a clinical trial headed by our clinical collaborator, Dr Hang Quach.

Honours and PhD Projects

Staff

  • A/Prof Louise Purton
  • Dr Mannu Walia
  • Dr ShuhYing Tan
  • Lenny Straszkowski
  • Dr Gavin Tjin
  • Clea Grace
  • Kelli Schleibs
  • Diannita Kwang
  • Dr Slavica Ninkovic

Publication Highlights

  1. Purton LE, Dworkin S, Olsen GH, Walkley CR, Fabb SA, Collins SJ, Chambon P. RARg is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J Exp Med 2006; 203:1283-1293.
  2. Walkley CR*, G. Haines Olsen*, S Dworkin, SA Fabb, J Swann, GA McArthur, SV Westmoreland, P Chambon, DT Scadden & LE Purton. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency. Cell 2007; 129: 1097-1110. *Equal first authors.
  3. Purton LE, Scadden DT. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 2007; 1:263-270.
  4. Wu JY*, Purton LE*, Rodda S, Chen M, Weinstein LS, McMahon AP, Scadden DT, Kronenberg HM. Osteoblastic regulation of B lymphopoiesis is mediated by Gsalpha-dependent signaling pathways. PNAS 2008; 105:16976-16981.
  5. Chee LC, Hendy J, Purton LE, McArthur GA. ATRA and the specific RARa agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells. Leukemia 2013; 27:1369-1380.
  6. Joseph C, Quach JM, Walkley CR, Lane SW, Lo Celso C, Purton LE. Deciphering hematopoietic stem cells in their niches: a critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell 2013; 13:520-33.
  7.  Quach JM, Askymr M, Jovic T, Baker EK, Walsh NC, Harrison SJ, Neeson P, Ritchie D, Ebeling PR, Purton LE. Myelosuppressive therapies significantly increase pro-inflammatory cytokines and directly cause bone loss. JBMR 2015; 30:886-897.
  8. Joseph C, Nota C, Fletcher JL, Maluenda AC, Green AC, Purton LE. Retinoic acid receptor γ regulates B and T lymphopoiesis via nestin-expressing cells in the bone marrow and thymic microenvironments. The Journal of Immunology 2016; 196:2132-2144.
  9. Hawkins ED, Duarte D, Akinduro O, Khorshed RA, Passaro D, Nowicka M, Straszkowski L, Scott MK, Rothery S, Ruivo N, Foster K, Waibel M, Johnstone RW, Harrison SJ, Westerman DA, Quach H, Gribben J, Robinson MD§, Purton LE§, Bonnet D§, Lo Celso C. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature 2016; 538:518-522. § Robinson, Purton and Bonnet are co-second last authors.
  10. Duarte D, Hawkins ED, Akinduro O, Ang H, De Filippo K, Kong IY, Haltalli M, Ruivo N, Straszkowski L, Vervoort SJ, McLean C, Weber TS, Khorshed R, Pirillo C, Wei A, Ramasamy SK, Kusumbe AP, Duffy K, Adams RH, Purton LE, Carlin LM, Lo Celso C. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 2018; 22:64-77.