MCRI Stem Cell Medicine's blood research is conducted by our Blood Cell Development and Disease laboratory, led by Professor Andrew Elefanty. It focuses on using human pluripotent stem cells toward modelling diseases of the blood system, developing new blood therapies, and generating cells for future replacement therapies.
Diseases of the blood can be due to 'overproduction' of blood cells, leading to leukaemias, or 'underproduction' of blood, leading to bone marrow failure. Leukaemia is a significant health problem in Australia. It is the 8th most common cancer in Australia, and nearly 4000 new cases will be diagnosed in 2018. The 5 year survival is 61%, and it is estimated that up to 2000 people will die from leukaemia in 2018. Leukaemia is the commonest cancer world-wide in children, and in Australia approximately 250 cases of childhood leukaemia are diagnosed each year,.
Bone marrow failure syndromes can be caused by inherited mutations in a variety of genes associated with DNA repair or blood formation, but the most common cause is the acquired form, termed aplastic anaemia, associated with a disordered immune system. Patients with bone marrow failure syndromes have a high risk of developing cancer, including leukaemia. It is estimated 160 young Australians are diagnosed with bone marrow failure syndromes each year, only half of whom will survive. Our laboratory at MCRI is focused on the differentiation of blood and endothelium from human pluripotent stem cells, with a view to understanding human development, modeling disease and finding new cures and, eventually, generating cells for therapeutic applications.
Deciphering the circuitry of human blood cell development
Our research program aims to make blood stem cells (called haematopoietic stem cells, or HSCs) from human pluripotent stem cells (hPSCs). These HSCs would be valuable for the treatment of leukaemia and other blood disorders. The ability to make these cells in the laboratory would also allow us to better study blood diseases and develop new treatment strategies.
We are currently able to make blood cells that are similar to those that develop in the early human embryo. We are further improving our methods to produce cells that even more closely mimic human HSCs, and have the ability to produce the whole blood system. We would like to replicate the bone marrow environment that houses developing HSCs in order to make a 'bone marrow factory' that makes blood cells.
Modeling childhood leukaemia
Although the treatment of childhood leukaemia overall has improved over recent years, the outlook for some children with some types of disease is still poor. We are studying leukaemia by genetically engineering hPSCs so that they carry the same mutations that are seen in the genes of children with leukaemia. We wish to use these mutated cells to identify new combinations of drugs that will improve the treatment options for children.
Modeling bone marrow failure
In bone marrow failure, insufficient blood cells are made in the bone marrow resulting in anaemia, bleeding and infections. We wish to enhance our knowledge of the causes of bone marrow failure diseases so that we can devise new treatment approaches. Some patients with bone marrow failure have mutations in key blood cell genes, which we can study by reproducing the mutation in hPSCs in vitro. In other patients, the mutation is not known and we are making reprogrammed stem cells from these patients (called induced pluripotent stem cells, or iPSCs) in order to study these cases further.
Ng ES, Azzola L, Sourris K, Robb L, Stanley EG, Elefanty AG. (2005) The primitive streak gene, Mixl1, is required for efficient haematopoiesis and BMP4-induced ventral mesoderm patterning in differentiating ES cells. Development, 132(5): 873-884.
Ng ES, Davis RP, Azzola L, Stanley EG and Elefanty AG. (2005) Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood, 106 (5): 1601-1603.
Ng ES, Davis R, Stanley EG and Elefanty AG. (2008) A protocol describing the use of a recombinant protein-based, animal product free medium (APEL) for human embryonic stem cell differentiation as spin embryoid bodies. Nature Protocols, 3(5): 768-776.
Pick M, Azzola L, Mossman A, Stanley EG and Elefanty AG. (2007) Differentiation of human embryonic stem cells in serum free medium reveals distinct roles for BMP4, VEGF, SCF and FGF2 in hematopoiesis. Stem Cells, 25(9): 2206-2214, 2007.
Gertow K, Hirst CE, Yu QC, Ng ES, Pereira LA, Davis RP, Stanley EG, Elefanty AG. (2013) WNT3A Promotes Hematopoietic or Mesenchymal Differentiation from hESCs Depending on the Time of Exposure. Stem Cell Reports, 1(1):53–65.
Ng ES, Azzola L, Bruveris FF ... Stanley EG, Elefanty AG. (2016) Generation of HOXA+ hemogenic vasculature from human pluripotent stem cells that resembles aorta-gonad-mesonephros. Nat Biotechnol. 34(11):1168-1179.