St Vincent's Institute

The regulation of blood stem cell self-renewal and differentiation

We are investigating how stem cells are influenced by two different regulatory pathways as follows:

1. The vitamin A receptor pathway 
   Our research has pioneered the different effects of the vitamin A receptors in 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. We now have evidence that the RARs have different effects in the production of bone cells. We are further exploring the roles of vitamin A and its receptors in blood cell and bone production. 
2. Influences of cell cycle regulators on blood cell production
   We are interested in understanding how the process of cell division is coupled to the fate of blood stem cells. For a stem cell to self-renew or to differentiate requires them to undergo division. Our recent studies have focused on understanding the roles of negative cell cycle regulatory genes (such as the retinoblastoma protein, pRb) in regulating blood stem cell fate. We are now exploring roles for the cell division cycle in other aspects of blood cell diseases, such as anaemia.

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 are determining how cells of the bone marrow microenvironment regulate blood cell production in both normal and diseased states. Two major projects currently in force in our labs are as follows:

1. Determining the contribution of the bone marrow microenvironment to blood cell diseases.
   Myeloproliferative diseases (MPDs) are blood cell diseases that are life-threatening and can progress to leukaemia. Patients who develop MPDs largely cannot be cured, mainly because there is very little understanding of how MPDs occur. MPDs are generally considered to arise from defects occurring in the blood cells. We have recently described two unique models of myeloproliferative-like diseases in which the MPDs are caused by cells of the bone marrow microenvironment. We are further exploring how the bone marrow microenvironment influences MPD development, and will determine if the bone marrow microenvironment can also contribute to the development of other blood cell cancers.
2. 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.

Epigenetic regulation of stem cells

Epigenetic modifications, including DNA methylation and post-translational histone modifications, are fundamental processes underlying the self-renewal capacity, cellular differentiation and lineage specification of different cell types. A primary focus of these studies is to determine the epigenetic profiles of bone stem cells. The goals of this project are to generate chromatin state maps for bone stem cells and more mature bone cells in different stages of normal development. The proposed studies will greatly enhance our understanding of the role of chromatin structure in bone stem cell self-renewal and fate commitment. The epigenetic blueprints obtained in this study will then be used to identify disease-based signatures, commencing with our well-established model of mouse osteosarcoma (outlined in project 4). We anticipate that the knowledge gained from these studies will be translatable into human cells for therapeutic purposes.

Modeling osteosarcoma (bone cancer)

Osteosarcoma is the most common tumour of bone. We have developed and characterized a unique model of this tumour based on our understanding of the human disease. This model closely mirrors the human disease in terms of histology, transcriptional profile, cytogenetics and metastatic dissemination. We are using this faithful model of human osteosarcoma to further understand the genetics of this disease as well as a pre-clinical model to explore new therapeutic approaches to treat both primary and metastatic disease.