Elucidating stromal regulation of hematopoiesis through syndecan-2

About This Grant

ABSTRACT Understanding the fundamental processes that underscore hematopoiesis is necessary to generate therapeutics that can correct hematopoiesis during disease or support hematopoietic regeneration during stress. The bone marrow microenvironment, or niche, supports hematopoiesis by providing cellular and acellular cues that influence hematopoietic differentiation, hematopoietic stem cell self-renewal, and the functional integrity of the bone marrow niche itself. Inadequate or inappropriate hematopoietic differentiation can lead to disease or death by depleting hematopoietic cell populations needed for organismal survival. Additionally, commonly used therapeutics like radiation and chemotherapy cause hematopoietic cell death and damage the bone marrow niche, leaving patients in a vulnerable state of hematopoietic insufficiency. The inability to restore hematopoietic homeostasis after radiation exposure puts patients at a heightened risk for developing deadly complications, such as infection or hemorrhage. Therefore, understanding how hematopoiesis is maintained and restored is of the utmost importance. Our previous studies showed that syndecan-2 (a specific heparan sulfate proteoglycan) expressed by hematopoietic stem cells promotes long-term hematopoietic stem cell self-renewal ability by supporting quiescence. The bone marrow niche is also a rich source of proteoglycans. Our preliminary data indicate that bone marrow mesenchymal stromal cells (MSCs) also highly express syndecan-2. Genetic depletion of syndecan-2 in MSCs using transgenic mouse models caused significant hematopoietic system imbalances in the peripheral blood at steady-state and after hematologic stress. In this application, we propose to elucidate how MSC-derived syndecan-2 regulates hematopoiesis in vivo. We will use a multi-scale approach to test the function of syndecan-2 at the molecular, cellular, and systemic scales by combining transgenic knockout mouse models and in vivo injury models with high-resolution bone marrow imaging and super- resolution imaging of MSCs. We will test the role of MSC syndecan-2 in hematopoietic differentiation, growth factor organization, and signaling. Because hematopoietic demands increase during states of hematopoietic stress, we will also test the function of syndecan-2 from MSCs in hematologic and niche regeneration from radiation injury. Successful completion of these aims will define the role of MSC-derived syndecan-2 in hematopoietic homeostasis and regeneration, providing foundational knowledge needed to leverage proteoglycans to correct or boost hematopoiesis during states of imbalance or stress.