Blood stem cells are responsible for the production of blood and are crucial for treating patients suffering from diseases related to blood cancer. Researchers are exploring ways of generating blood stem cells in the laboratory, for example to overcome the shortage of matching blood stem cell donors.
CRM researchers led by Dr Katrin Ottersbach are investigating how blood stem cells first emerge and develop in the early embryo. Better understanding of the natural process will bring us closer to developing novel protocols for the generation of blood stem cells in the laboratory.
In their latest study, published in the Journal Blood, they found that the cell signalling molecules interleukin 3 and thrombopoietin regulate the expansion and survival of blood stem cells. They do so using the JAK2 and Pi3k protein signalling pathways. The researchers found that intact Jak2 signalling was essential for the production of the first blood stem cells in the embryo.
The so-called ‘JAK2V617F’ mutation is one of the causes for myeloproliferative blood disorders (MPD). The mutation results in the generation of an overactive version of the enzyme ‘JAK2 kinase’ that, when present in adult blood stem cells, causes DNA damage and defects in blood stem cell function and self-renewal.
This study, however, revealed that embryonic blood stem cells are completely resistant to the JAK2 mutation.
Dr Katrin Ottersbach explained:
Our work identified two cytokines that regulate blood stem cell expansion and survival. Our results strongly suggest that these cytokines can be used to increase blood stem cell production in a laboratory setting.
We also showed that embryonic blood stem cells have unique properties that make them resistant to mutations that cause DNA damage, self-renewal defects and myeloproliferative blood disorders in adults. Identification of the underlying molecular determinants for this resistance gives us important clues for the development of new treatments for myeloproliferative blood disorders.
The work was carried out in collaboration with the Department of Haematology, University of Cambridge, the Cambridge Institute for Medical Research, and the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. It was funded by the Medical Research Council, the Kay Kendall Leukaemia Fund, Bloodwise, the British Society for Haematology and the Wellcome Trust.
- Mascarenhas MI, Bacon WA, Kapeni C, Fitch SR, Kimber G, Cheng SW, Li J, Green AR, Ottersbach K. 2016. Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation. Blood. 2016 Feb 10. pii: blood-2015-08-664631. PMID: 26864339 [Epub ahead of print].