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Regeneration of the blood system through the transplantation of blood-forming stem cells (commonly referred to as bone marrow transplantation) is an effective treatment for a range of blood cell diseases, including leukemia. The transplantation of blood-forming stem cells and specific blood cell types is already being used in the clinic or under investigation for the treatment of an expanded list of diseases, such as cancers, autoimmune diseases and inflammation. Cells for these therapies are currently obtained from immune-matched donors or from the patients themselves. Although effective, reliance on donor and patient-derived cells limits the number of patients that can be treated and the benefit of these transplantation-based therapies. The generation of blood-forming stem cells and specific blood cell types from human pluripotent stem cells (hPSCs) would provide a new and potentially unlimited supply of these cells for treating a much broader patient population.
Using insights from blood cell development in different organisms, the Keller lab has successfully modelled human hematopoietic development from hPSCs differentiated in vitro. Through manipulation of specific signalling pathways, they have demonstrated that it is possible to generate the two major hematopoietic programs — primitive and definitive — which are known to develop in the embryo. While the main function of primitive hematopoiesis is to generate the cohort of blood cells required to sustain embryonic life, recent studies have shown that this program also contributes to a specialized immune cell population, the tissue-resident macrophage that persists in different organs into adulthood. These macrophages are thought to play important roles in maintaining normal organ function. Definitive hematopoiesis gives rise to all the hematopoietic cell types found in the adult, including the hematopoietic stem cell (HSC). Through our ability to specify these two programs, we have been able to develop protocols for the generation of most of the hematopoietic cells found in the embryo as well as in the adult. Additionally, we have been able to identify developmentally staged progenitors that display the properties of the progenitors that give rise to the HSC in the embryo. These advances have brought us an important step closer to generating hPSC-derived HSCs, immune cells and tissue-resident macrophages for the development of new cell-based therapies to treat different diseases.
Current projects include: