Blood Development
Using human pluripotent stem cells to understand blood development, model blood diseases, and generate blood stem cells to treat children with leukaemia and bone marrow failure who lack a suitable donor.
Our laboratory uses the differentiation of human pluripotent stem cells to study the development of blood cells and diseases of the blood system.
The Blood Development laboratory uses the differentiation of human pluripotent stem cells to study the development of blood cells and diseases of the blood system. This work will help to find cures for diseases such as leukaemias (cancers of the blood) and bone marrow failure, where insufficient blood cells are made. These illnesses represent a major cause of death in children.
Our ability to treat these children will be enhanced by increasing knowledge of how these illnesses develop. Mimicking the diseases in the laboratory will permit testing of new combinations of drugs that could more effectively treat leukaemias or stimulate blood growth in children with bone marrow failure.
Blood stem cell transplantation is an additional component of therapy for some children with blood diseases, but not all children who would benefit from this treatment can find a suitably matched donor, ideally a sibling.
Transplantation of imperfectly matched blood stem cells frequently leads to graft versus host disease in which donor immune cells attack the patient, possibly resulting in serious illness or death. For children who lack a matched blood stem cell donor, we could prevent this complication if we could transplant child-specific blood stem cells made in the laboratory.
Our studies will teach us more about blood formation in health and disease, helping us to discover new drug treatments and develop new blood stem cell therapies for sick children and adolescents.
Our projects
Deciphering the circuitry of human blood cell development
Our research aims to make blood stem cells (haematopoietic stem cells, or HSCs) from human pluripotent stem cells. These in vitro generated HSCs would be valuable for the treatment of leukaemia and other blood disorders and allow us to better study blood diseases and develop new treatment strategies.
We are currently able to make blood cells similar to those that develop in the early human embryo. We are further improving methods to produce cells that more closely mimic human HSCs, with 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.
Modelling 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 human pluripotent stem cells 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.
Modelling 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 human pluripotent stem cells in vitro. In other patients, the mutation is unknown and we are making reprogrammed stem cells from these patients (called induced pluripotent stem cells, or iPSCs) in order to study these cases further.
Funding
- Novo Nordisk Foundation Centre for Stem Cell Medicine
- National Health and Medical Research Council (NHMRC)
- CSL Limited
Collaborations
- Hanna Mikkola, Univerity of California, Los Angeles, California, USA
- Constanze Bonifer, University of Birmingham, UK
- Chris Sturgeon, Icahn School of Medicine at Mount Sinai, New York, USA
- Stuart Mannering, St Vincent’s Institute of Medical Research, Melbourne, Australia
- Andrew Deans, St Vincent’s Institute of Medical Research, Melbourne, Australia
- Collaborations with scientists at MCRI, Shireen Lamande, John Bateman, Tony Pennington, Rachel Conyers.
Featured publications
- Differentiation of human embryonic stem cells to HOXA(+) hemogenic vasculature that resembles the aorta-gonad-mesonephros.
Nature biotechnology 34, 1168-1179 (2016). Ng, E.S. et al. - Human yolk sac-like haematopoiesis generates RUNX1-, GFI1- and/or GFI 1B-dependent blood and SOX17-positive endothelium.
Development 147, dev193037 (2020). Bruveris, F.F. et al. - Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells.
Cell reports 31, 107691 (2020). Nafria, M. et al. - 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, 768-776 (2008). Ng, E.S., Davis, R., Stanley, E.G. & Elefanty, A.G. - Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood 106, 1601-1603 (2005).
Ng, E.S., Davis, R.P., Azzola, L., Stanley, E.G. & Elefanty, A.G.