From the earliest stages of development, blood vessels and nerves form together and connect distant sites of hematopoiesis. As we learn more, we are finding that blood cells share many signaling pathways with neurons. We are beginning to understand that there is communication between the blood and nervous systems. We now know that the sympathetic nervous system (SNS) innervates a specialized microenvironment called the niche that is home to hematopoietic stem cells (HSCs). One signal from sympathetic neurons is norepinephrine that is bound by -adrenergic receptors on stromal support cells and HSCs themselves. This signal instructs stromal cells to down-regulate the ligand CXCL12, one of the most important retention signals for HSCs in the niche, which express the cognate receptor CXCR4. HSCs are then released into circulation or mobilized out of the bone marrow. This cycle of mobilization and engraftment back into the niche is regulated daily by the SNS and follows circadian rhythms. The functional significance of bone marrow niche innervation has recently become apparent, as sympathetic nerve damage can contribute to the progression of some blood diseases. Many patients with myeloproliferative neoplasms have HSC with a JAK2(V617F) mutation that drives interleukin-1 production. HSCs that overproduce this cytokine actually cause SNS injury within the niche that ultimately accelerates the disease (Arranz et al. Nature 2014). The goal of this research plan is to understand the mechanisms of HSC niche regulation by the nervous system and to find new neuroregulators of HSCs and the niche. The zebrafish and mouse will be used as complementary model organisms. Novel HSC-specific transgenics and high resolution microscopy has established the zebrafish as an important HSC niche model (Tamplin et al. Cell 2014). The high degree of conservation between zebrafish and mammals means findings can be easily translated. The goal of this research is to recreate a regulatory environment ex vivo that will allow expansion and maintenance of HSC prior to clinical transplantation. My long-term career goal is to lead my own biomedical research group at a major research institution. My strong background in developmental genetics and postdoctoral training in zebrafish hematopoiesis has been excellent preparation for this proposed research. I have been very fortunate to find an ideal training environment at Boston Children's Hospital and Harvard Medical School. My mentor Dr. Leonard I. Zon is highly supportive of my research and is helping me prepare for the transition to independent investigator. I have benefited from mentoring Harvard graduate and undergraduate students in the lab, and three technicians. My co-mentors Drs. George Q. Daley, Charles Lin, and Christopher A. Walsh have offered their expertise in the topics of mammalian HSC assays, live imaging of the HSC niche, and neurobiology, respectively. This award will allow me to continue receiving their guidance and support before starting my own independent research program that will explore the interface between the hematopoietic and nervous systems.
Hematopoietic stem cell transplantation is a curative therapy for many patients with blood diseases and disorders, however it is not always possible to identify a matched donor. An alternative source of stem cells is umbilical cord blood but the low number of cells found in each cord is a limiting factor, therefore an approach to expand cord blood stem cells has the potential to improve transplantation efficiency and patient survival. An exciting finding is that hematopoietic stem cells are regulated by signals from the nervous system and I will explore the possibility that neuromodulators could be used to expand and maintain stem cells prior to transplantation.
|Blaser, Bradley W; Moore, Jessica L; Hagedorn, Elliott J et al. (2017) CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment. J Exp Med 214:1011-1027|