People with leukaemia could be helped by new research that sheds light on how the body produces its blood supply.
Scientists are a step closer to creating blood stem cells that could reduce the need for bone marrow transplants in patients with cancer or blood disorders.
Enabling scientists to grow the stem cells artificially from pluripotent stem cells could also lead to the development of personalised blood therapies, researchers say.
Blood stem cells are found in bone marrow and produce all blood cells in the body. These cells – known as haematopoietic stem cells (HSCs) – help to restore blood supply in patients who have been treated for leukaemia.
Researchers used a mouse model to pinpoint exactly how HSCs develop in the womb. They showed for the first time how three key molecules interact together to generate the cells, which are later found in adult bone marrow.
The discovery could help scientists to recreate this process in the lab, in the hope that HSCs could one day be developed for clinical use.
Scientists say this fundamental understanding of early development may also have an impact on other diseases that affect blood formation and supply.
Professor Alexander Medvinsky, of the University of Edinburgh’s Medical Research Council Centre for Regenerative Medicine said:
There is a pressing need to improve treatments for diseases like leukaemia and this type of research brings us a step closer to that milestone. The more we understand about how embryos develop these blood stem cells, the closer we come to being able to make them in the lab.
The research has been published in Nature Communications. The study was funded by the Wellcome Trust, Bloodwise, BBSRC, MRC and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007–2013.
Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells. 2016. Souilhol C, Gonneau C, Lendinez JG, Batsivari A, Rybtsov S, Wilson H, Morgado-Palacin L, Hills D, Taoudi S, Antonchuk J, Zhao S and Medvinsky A. Nature Communcations. Published online 9 March 2016. DOI: 10.1038/NCOMMS10784.
Blood stem cells, known as haematopoietic stem cells (HSCs), reside in bone marrow and generate all blood cells in the body. HSCs are not exhausted during lifespan as they can divide and produce copies of themselves. Clinical transplantations of HSCs can restore normal blood formation in patients with blood deficiencies (~50,000 patients/year) including those who underwent chemo- and radiotherapy for treatment of such diseases as leukaemia. However, donor shortages pose a significant problem: only 20-60% of patients on registers find a good genetic match for transplants, which affects treatment options, efficiency and outcomes.
Despite the importance of HSCs in normal human development, physiology and for clinical applications, our understanding of the mechanisms underlying production of HSCs during development is insufficient. This is particularly evident by the inability to generate HSCs in laboratory conditions.
Our laboratory investigates mechanisms used by the embryo to produce HSCs, so that in future the shortfall in supplies for clinical transplantations can be addressed. During embryo development, HSCs mainly emerge in a particular “ventral” location within the region called AGM. In this study, we found that complex inductive interactions between cells of the ventral location and surrounding tissues are necessary for effective formation of HSCs. We found that collaboration between 3 molecules (Sonic Hedgehog (Shh), Stem Cell Factor (SCF) and Noggin), secreted by different parts of the AGM region, are involved in these inductive interactions and are important HSC emergence.
This study significantly adds to our fundamental understanding of HSC development and will help to design protocols for production of HSC in laboratory conditions.
Main findings of the paper
- Inductive interactions between three sub-regions of the embryonic AGM region are needed for effective generation of haematopoietic stem cells (HSCs).
- These inductive interactions are mediated by collaboration between three genes differentially expressed in these sub-regions of the AGM region: Sonic Hedgehog (Shh), Stem Cell factor (SCF) and Noggin.
- Bone Morphogenetic Protein, proposed previously to stimulate HSC development in mouse embryo at mid-gestation, in fact needs to be downregulated during HSC development.