Haematopoietic stem cells (HSCs) are the source of all blood and immune cells. More than 50,000 HSC transplantations (as bone marrow transplants) are performed globally each year, saving tens of thousands of lives. However, these are limited by the availability of adequate matched donors; in addition, today’s limited understanding of their molecular interactions inhibits our ability to expand their use and replicate their function.
Dr. Gazit’s group works on three main projects with HSCs that can have applicative relevance: Autologous HSC transplants are currently the most frequently type of clinical use, and one project focuses on the direct reprogramming of normal blood cells back to HSCs for clinical use. Such reprogrammed HSCs are urgently needed for many patients that cannot find a matched donor. Under physiological conditions, mature cells are generated from stem cells in an irreversible process (blood cells cannot form new stem cells), however recent methodological advances have provided ways to reprogram differentiated cells back into stem cells. After discovering transcription factors that induce HSC-like activity in mice, the researchers aim to improve this process and ultimately translate such findings into humans. With the identified as well as with additional predicted factors, their goal is to validate the ability to reprogram adult blood cells directly into multipotent and transplantable HSC-like cells.
The second project focuses on leukemia, a severe, life-threatening disease affecting hundreds of thousands of children and adults. Significant advances in treatments offer complete or partial cures for some types of leukemia, but there are many that remain untreatable. Animal models provide the opportunity to study the disease, and its initiation, progression, and effect on the biology and physiology of a living creature. Moreover, they also serve as a viable platform for the development and assessment of novel therapies. However, currently the availability of animal models is limited and many of them lack a competent immune system. As such, there are inherent limitations regarding the accuracy of these models, since a leukemia patient has an immune system and an immune history, even if it isn’t currently functioning correctly. Notably, harnessing the immune system against cancer is a major frontier of cancer treatments today. Dr. Gazit’s group is using an advanced lentiviral system for simultaneous overexpression of different transcriptional factors in order to generate a series of leukemia models that closely simulate human Acute Myeloid Leukemia (AML) or Chronic Lymphocytic Leukemia (CLL). These models will enable increased understanding of disease initiation and progression, and will be in the development of new treatments.
The third project centers on the identification of HSC receptors that directly respond to immune mediators and their responses to infection. Immune stimulation enhances the production of the various immune cells that ultimately come from HSCs in the bone marrow. However, there is limited knowledge about the relevant HSC receptors that directly respond to immune mediators, and functional studies are needed to understand their responses to infection. Utilizing specific activators of HSC function will pave the way in being able to guiding our own stem cells and the source of all blood and immune cells. The researchers achieve this by using a unique HSC-reporter mouse, in which a fluorescent reporter labels HSCs, in normal and under stress conditions. In doing so, they are able to track and follow stem cells during infection, aiming a better understand of how they are activated and what the consequences of a chronic-infection might be. Intriguingly, the total numbers of HSCs probably increase with age, while their activities diminish, thus limiting immunization and regeneration in the elderly, despite possibly having more stem cells. Mechanistic understanding will point to new ways for modulating our own HSCs to elicit an adequate response when needed while preserving their lifelong potency.