Mechanisms of Hematopoietic Stem Cell Reprogramming by Type II Interferon

Project Summary A hallmark of the hematopoietic system is the ability to respond to inflammatory challenges. Central to this response are hematopoietic stem and progenitor cells (HSPCs), which balance self-renewal and differentiation programs to maintain stable blood cell output. In response to acute inflammation, such as infection, pro- inflammatory cytokines activate HSPCs to rapidly augment innate immune cell production. Although initially critical for pathogen control, persistent and non-productive inflammation can drive HSPC dysregulation and stem cell loss, a key contributor to bone marrow failure syndromes, acquired neutropenia, and hematologic malignancies. Certain inflammatory stimuli, including the mycobacterium BCG, induce durable epigenetic and transcriptional reprogramming in HSPCs which is transmitted across differentiation to mature innate immune cells with enhanced effector function upon restimulation. These findings suggest HSPCs can act as a reservoir of inflammatory memory with functional consequences in differentiated immune cells, yet the cytokine signals and molecular programs that establish HSPC memory are poorly understood. This proposal aims to dissect the mechanisms through which Type II Interferon (IFNG) signaling in response to BCG establishes durable memory programs in HSPCs and their innate immune progeny cells. In Specific Aim 1, we will characterize the cellular targets of IFNG signaling within the bone marrow (BM) niche required for HSPC reprogramming, then define the contribution CD4 T lymphocytes to this response. In Specific Aim 2, we will apply single cell multi-omics and epigenomics approaches to identify the epigenetic mechanism by which IFNG signaling establishes durable memory programs in HSPCs, then trace the inheritance of these programs across differentiation to innate immune cells. This project is ideal for a physician-scientist in training, given its blend of cellular immunology and high-throughput sequencing approaches to dissect the durable impact of inflammation on the hematopoietic system, along with the potential to uncover novel therapeutic targets to address stem cell dysfunction in hematologic disease and augment innate immunity. With the mentorship of my sponsor, co-sponsor, collaborators, thesis committee, Tri-I MD-PhD program leadership, and the support of this fellowship, I will be well prepared to pursue and achieve my goal of being a physician-scientist and independent investigator.