Thursday, February 13, 2025
2/13/2025
PROJECT DESCRIPTION Hematopoiesis is a demand-adapted system in which self-renewing hematopoietic stem cells (HSC) and downstream hematopoietic stem and progenitor cells (HSPC) integrate signals from their bone marrow (BM) niche microenvironment to adapt blood production to the needs of the organism. In regenerative conditions, this results in the transient engagement of stereotypical emergency myelopoiesis (EM) pathways, which consist of transcriptional, epigenetic, and metabolic mechanisms that do not usually operate under native conditions, but act to prioritize rapid production of myeloid cells at the expense of other blood lineages before returning to ho- meostasis. In contrast, in maladaptive contexts like chronic inflammation, leukemia, or aging, EM pathways are constitutively engaged and drive overproduction of myeloid cells that often have altered effector function. Our previous work established EM pathways as a distinct trajectory of myeloid development that depends on unique HSPC signaling states and cell behavior. Our proposed work in this new NHLBI OIA application will build upon the fundamental biology of EM pathways that we have uncovered to 1) explore the importance of EM pathway activation for essential immune responses such as trained immunity, myeloid cell heterogeneity, and immuno- suppressive tumor microenvironment; 2) establish a novel BM-on-chip platform to model the environmental crosstalk between niche and HSPCs in regulating EM pathway activation; and 3) translate our finding of EM pathway activation in mice into the human system. We will use state-of-the-art experimental approaches focusing on the study of defined hematopoietic populations and emerging properties of the BM niche microenvironment, and will take advantage of the power of transcriptional and epigenetic single cell profiling strategies and spatial imaging approaches, to ask novel questions that will push the boundary of what is currently known regarding the regulation of myelopoiesis in adaptive and maladaptive contexts in both mice and humans. Collectively, these studies are paradigm shifting as they will extend our current understanding of myeloid regeneration mechanisms into new, uncharted territories with broad translational applications to fight immune deregulations and treat solid cancers and blood disorders. .
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