Project Summary: The regeneration of blood and immune cells relies on hematopoietic stem and progenitor cells (HSPCs) that reside in the bone marrow. HSPCs not only sustain homeostasis of the blood pool by constantly producing the precise amounts and types of blood cells as needed, but they also respond rapidly to injuries such as bleeding or infection. During these processes, HSPCs constantly sense and react to signals from various bone marrow cell types. Their spatial proximity to the sources of these signals change as they migrate during differentiation and proliferation within the tightly packed bone marrow. The spatial organization of individual HSPCs forms a dynamic landscape that modulates their intercellular communication. In the proposed project, we will study the dynamic spatial configuration of HSPCs during hematopoiesis and its impact on intercellular signaling, proliferation, differentiation, and injury response. The central hypothesis of this proposal is that cell fate transitions during hematopoiesis are associated with the migration of HSPCs through distinct bone marrow micro-environments where they are exposed to signals that promote their expansion and differentiation. We propose to use MEMOIR and seqFISH technologies to (1) map the spatial organization of HSPCs in the bone marrow, (2) investigate the dynamic changes of HSPCs’ spatial positioning during hematopoiesis and upon the demand of a specific blood cell type, and (3) determine the impact of HSPCs’ spatial context on their intercellular signaling and fate choices. Our findings will introduce a novel, spatial perspective of blood and immune cell regeneration and significantly impact many biomedical fields including immunology, hematology, tissue engineering, aging, and cancer. Moreover, this work will provide an experimental and conceptual framework for analyzing spatially defined intercellular communication in other tissue contexts.

Project Narrative: In this proposal, we will investigate how stem and progenitor cells interact in the bone marrow with other cells to produce blood. This research can help improve the diagnosis and treatment of many diseases including bone marrow failure, leukemia and lymphoma, and provide new insights into blood and immune cell regeneration. In addition, our findings can help improve the bone marrow transplantation and develop new treatment strategies in regenerative medicine.