Dynamics and plasticity of the hematopoietic stem cell niche

About This Grant

Project summary/Abstract Hematopoiesis is a highly regulated process fueled by hematopoietic stem cells (HSCs) and progenitors in response to physiological and pathological changes throughout life. During development, the system quickly expands to provide increasing numbers of blood cells for the growing tissues and organs. In regeneration, HSCs re-establish the hematopoietic hierarchy and supply lost blood cells to restore tissue function. In pathological conditions, dysregulated hematopoiesis drives disease progression. A detailed cellular and molecular understanding of the mechanisms of dynamic hematopoiesis is key to intervening in these processes for therapeutic benefits. Although the niche critically regulates HSCs and hematopoiesis, how the niche is dynamically regulated to adapt to the distinct demands in the ever-changing conditions is not clear. Our previous work has identified key cellular components of the niche in the bone marrow and developing liver, allowing precise studies of niche dynamics in these organs. Our recent work has also revealed surprising cell fate plasticity in the bone marrow niche. The proposed work in this application builds on these findings to 1) define niche dynamics and plasticity in development, regeneration, and hematological disease, 2) uncover the mechanisms that regulate these processes, and 3) harness the mechanisms to enhance niche function and boost blood cell production. We will use several novel mouse models generated in the lab to study the function of key pathways in regulating niche dynamics and cell fate plasticity. We will employ single-cell transcriptomics, imaging, metabolic analysis, functional studies, and other cutting-edge approaches to understand how these key pathways regulate niche dynamics and plasticity. Collectively, these experiments will uncover novel mechanisms that regulate niche cell dynamics and plasticity with broad implications for better treatment of blood diseases. They may lead to transformative strategies for boosting blood cell production by enhancing niche function.