Characterization of inflammation driven responses in human hematopoietic stem and progenitor cells. (360G-Wellcome-107630_Z_15_Z)

The existence of functionally distinct haematopoietic stem cell (HSC) subsets is crucial for steady-state blood production and efficient recovery from injury. However, if and how these HSC subsets differentially respond to stress signals has not been addressed. Moreover, some HSC stress responses have been shown to be species-specific, underlining the necessity of studying human cells directly. My own transcriptional profiling of highly purified human long-term (LT-) and short-term (ST-) HSC ind icates that these HSC subsets may be differentially sensitive to a range of pro-inflammatory signals. As a handful of inflammation cues are known to directly affect HSC or progenitor cell function during development and infection, my specific objectives are to: 1) identify novel pro-inflammatory signals that act directly on human HSC subsets; 2) define how they alter HSC function; 3) determine through which molecular mechanisms this happens. This candidate-identification approach carried out on cells from healthy donors will be complemented with a comprehensive characterization of the inflammatory milieu, functional responses and transcriptional profiles of HSC and progenitor cells isolated from patients with chronic inflammatory diseases. Altogether, I expect these studies to provide new insights on the impact of inflammation on HSC biology and its contribution to disease.