Sir Henry Dale Fellow
Research themes:Stem Cell, Haematopoiesis, normal and malignant
Description of research
Life long production of all blood cell types is guaranteed by haematopoietic stem cells (HSC) through their ability to give rise to other HSC (self-renewal) as well as progressively more restricted cell types (differentiation). HSC are the best characterised stem cell type, owing to decades of intensive studies almost exclusively in model systems. These studies have revealed many stem cell properties, such as their infrequent division (quiescence) and have highlighted cellular and molecular routes that lead to the formation of mature blood cell types. It is almost taken for granted that what is true in small mammals will be conserved in humans. However differences in size, metabolism and longevity between human and animal models impose different demands on the blood system and suggest that there may be species-specific characteristics of HSC. Identifying these differences is a very important step to translate basic research findings to the clinic. Thus, the Laurenti group research focuses on primary human haematopoietic samples. Our goal is to understand the unique functional properties and molecular circuits of human HSC and how these are perturbed in disease.
Human HSC functional properties and their transcriptional make-up are unique compared to that of other hematopoietic cell types. When HSC differentiate into more committed progenitors, there are gradual changes in gene expression that translate into distinct usage of signalling routes, metabolic pathways, cell cycle properties (Nature Immunology 2013) and unfolded protein response (Nature 2014). Altogether these molecular circuits endow HSC with unique functional properties compared to their immediate progeny. Human HSC also seem to have evolved mechanisms subtly distinct from that of other species to ensure life-long blood production. In particular in injury or stress related contexts, the molecular basis for these processes is currently unknown. By using genome-wide profiling and functional assays, we aim to identify the changes, molecular and functional, triggered by stresses that these HSC are exposed to, both physiologically and in pathological conditions. This is part of an ongoing effort to understand the molecular networks of human HSC in homeostatic (Nature Immunology) and stress conditions.
Our particular areas of interest are:
- Understanding how quiescence is maintained in normal HSC.
- Understanding how HSC commit to a particular lineage.
- Defining how human HSC respond to stress.
As perturbations of the normal responses to these factors are considered stepping stones for leukaemogenesis, knowledge of these HSC specific responses to stress will prove important to understand how leukaemia arises.
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Keywords: Stem cells, progenitor cells, haematopoiesis, genome wide molecular approaches
Clinical conditions: Acute myeloid leukaemia
Methodologies: Isolating rare stem and progenitor cells, genome wide profiling, functional assays