The Trowbridge Lab

Why and how do hematopoietic stem cells age?

Hematopoietic stem cells (HSCs) are highly specialized cells that reside in the bone marrow and are required for lifelong production of all blood and immune cell types. During aging, intrinsic changes within HSCs (including epigenetic regulation, proteostasis and metabolic alterations) as well as extrinsic changes within the bone marrow microenvironment (including production of soluble growth factors and cytokines) contribute to the decline in function of the blood system. We are using single cell approaches such as single cell RNA-seq and ATAC-seq, single cell proteomics and metabolomics, as well as high-resolution imaging of the bone marrow and lineage tracing approaches to dissect the cellular and molecular drivers of HSC aging. In addition, we are examining heterogeneity between genetically identical individuals as well as genetically diverse mice as a model of human biological aging. Our goal is to identify cell types and mechanisms that serve as points of intervention to prevent or delay functional hematopoietic decline during aging.

What causes increased risk of blood cancer with aging?

HSCs and their progeny that carry certain somatic mutations providing them with a competitive advantage in the bone marrow are able to expand in a process termed clonal hematopoiesis. This process is a natural consequence of aging and yet the extensive nature of this phenomenon in the human population has only recently become appreciated. While clonal hematopoiesis itself is benign, a higher burden of clonal hematopoiesis is associated with increased risk of aging-associated diseases, including blood cancers and cardiovascular disease. Understanding the molecular drivers of clonal hematopoiesis, namely why certain somatic mutations provide a selective advantage in specific contexts, has the potential to improve assessment of blood cancer risk, as well as reduce the risk for progression from clonal hematopoiesis to blood cancer. Our laboratory is working towards these goals through development and utilization of novel in vivo-based modeling systems to understand how clonal hematopoiesis contributes to blood cancer and other aging-associated diseases, and interrogating the roles of the bone marrow microenvironment, specific inflammatory factors, immune cell regulation, senescence, and metabolic changes as candidate drivers of clonal hematopoiesis.

How does aging blood impact the brain?

Ample evidence supports that a compromised blood-brain barrier caused by aging and disease permits transit of certain blood cells into the brain. Our laboratory is interested in what these blood cells can do in the brain with respect to their contribution to microglia, which is a type of central nervous system-resident immune cell. In collaboration with other laboratories at JAX with expertise in neurobiology, we are developing and utilizing novel in vivo modeling systems to determine the extent to which circulating blood cells could be manipulated and used as a reserve population for enhancing the brain’s natural regenerative ability. We are also exploring how mutations in the blood, such as in clonal hematopoiesis, impact the identity and function of cells that transit into and take up residence within the brain.