Role of macrophages in remodeling hematopoietic stem cell clonal architecture and in progression from clonal hematopoiesis to MDS
EvansMDS Discovery Research Grant 2019
Myelodysplastic syndromes (MDS) are blood disorders arising from mutant abnormal blood stem cells. Little is known about how cell around the blood stem cells in the bone marrow affect the initiation of MDS. We propose to study the role of macrophages in this process using the zebrafish animal model. Zebrafish are vertebrates that have conserved blood and immune systems compared to humans. They offer a unique system to directly visualize cell-cell interactions, to trace the production of various blood cell subtypes and to test functions of these cells. From previous studies in mice, it is known that macrophages that live in the bone marrow have an important role in maintaining the function of blood stem cells. However, the exact role that macrophages may have in disease states is unknown and has never been studied. We have observed that in developing zebrafish embryos blood stem cells have close contact with macrophages. We believe that this interaction is critical for the correct function of stem cells. The presence of macrophages in the environment of stem cells not only helps their survival, but also determines the diversity of the blood stem cell pool. When we eliminate macrophages from the stem cell environment, we note a significant loss of stem cell diversity. Reduced stem cell diversity can contribute to the initiation of blood disorders. Thus, macrophages could potentially play an important role in blood diseases that arise from abnormal blood stem cell pool diversity, a state known as clonal hematopoiesis. Our proposal plans to test this through a series of experiments and define the role of macrophages in clonal hematopoiesis and MDS development. Understanding how macrophages contribute to MDS will offer new ways of approaching MDS treatments that target cells other than the abnormal stem cells themselves and complement already existing therapies. We will use the zebrafish to screen for compounds that change the macrophage-stem cell interactions by directly visualizing this contact through imaging. The goal of our studies is to improve our understanding of MDS initiation and to identify novel drugs for prevention and treatment of MDS.