Hematopoiesis in Cardiovascular Disease

Massachusetts General Hospital, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Leukocytes are descendants of hematopoietic stem and progenitor cells (HSPC) and are made in the bone marrow. Innate immune cells defend us against pathogens but may also attack cardiovascular tissues, thereby producing inflamed atherosclerotic plaques, organ ischemia and failing myocardium. In the era of rapid reperfusion and statin therapy, inflammation dominates the residual risk of cardiovascular disease (CVD) and thus decisively contributes to the pathogenesis of contemporary myocardial infarction, which stubbornly clings to the top position in mortality statistics. Because inflammation is not currently targeted by cardiovascular clinical care, this unused opportunity for immunotherapy, which shows great promise in autoimmune and oncological diseases, is the next frontier in treating ischemic heart disease. To address this large unmet clinical need, we propose to go to the root of inflammation: leukocyte production, i.e. hematopoiesis. Close interactions exist among hematopoiesis, white blood count and cardiovascular death. Altered hematopoiesis changes production rates and phenotypes of innate immune cells that may consequently protect or attack cardiovascular organs. Conversely, hematopoiesis is influenced by cardiovascular risk factors and disease. For instance, hematopoietic tissues are exquisitely vascularized and therefore intimately connected to blood-borne information. Recent data indicate that hyperlipidemia and acute MI activate the entire hematopoietic tree, including upstream stem cells. However, despite the well established association between leukocytosis and CVD, surprisingly little is known about the marrow's role in this setting. This knowledge gap arose from the traditional separation of the cardiovascular and hematology disciplines. Even today there are few truly interdisciplinary teams studying hematopoiesis in CVD. The scientists joining forces in this application have been building the missing link between the involved fields by connecting leaders in hematology (Scadden), innate immunity (Swirski), CVD (Nahrendorf), evolutionary dynamics, lineage tracing and genetics (Naxerova), gene editing (Kleinstiver) and imaging (Lin). This unique combination of complementary expertise creates the synergy and critical mass needed to study the bone marrow as a driver of cardiovascular mortality, our unifying scientific theme. As in the successful first funding period, we will continue to organize our team into four projects and three cores that jointly pursue our overall mission from two complementary vantage points: 1. What stem cell-intrinsic pathologies, including genetic and epigenetic alterations, cause leukocytosis and inflammation in cardiovascular organs? 2. How does CVD change both hematopoiesis and the phenotype of produced leukocytes? The four projects will pursue both perspectives collaboratively while focusing on the common end point of increased output of inflammatory immune cells that damage the arterial wall and heart. Innovative cores, which support all four projects, will continue to develop and provide the diagnostic and therapeutic means to pursue this mission.