Cellular and molecular mechanisms of stem and progenitor cell development during homeostasis and after injury

About This Grant

Project Summary/Abstract: Tissue homeostasis requires the precise control of the development of differentiated cell types from multipotent stem and progenitor cells (SPCs). This balance is regulated by signals originating from multi-tissue niches or SPCs themselves, which affect SPC development. Increasing data supports that these normal developmental processes can be aided or disrupted by inflammatory signal transduction pathways. While prior studies using whole animal knockouts identified the role of inflammatory signaling pathways in HSPC differentiation, open questions remain about the relative contributions of specific cell types to the observed phenotypes and the downstream targets of these pathways. The proposed research program uses the Drosophila melanogaster blood system as a model to address unresolved questions about how multiple cell types found within SPC niches use inflammatory signaling pathways to control the balance between SPCs and differentiated cells during homeostatic development and after injury. As blood SPCs differentiate they make fate choices between alternate paths of development, specifically between distinct intermediate and differentiated cell types, which in turn produce signals to influence the balance between SPC maintenance and differentiation. One goal of the proposed research is to address open questions about how the inflammatory signals activated by injury are propagated through distant niches to control the balance between SPCs and differentiated cells, and how these injury-induced changes influence wound healing. Another goal is to address unresolved questions about how pro-inflammatory signaling pathways influence normal SPC development, specifically which cell types and downstream targets are involved. Tissue damage is a hallmark of many human diseases including atherosclerosis and type 2 diabetes. These inflammatory diseases are also associated with disruption of normal SPC biology in multiple organ systems and increased likelihood of developing diseases that result from SPC dysfunction. Thus, determining the molecular mechanisms required for homeostatic tissue development and understanding how differentiation and SPC biology are changed by tissue damage and inflammatory signaling will provide information that gives insight into disease-related SPC dysfunction.