2006 – STEM CELL BASED HETEROGENEITY OF INTERFERON SIGNALING DURING HEMATOPOIETIC DEVELOPMENT

Inflammation has a great impact on an organism. In order to protect the hematopoietic system from exhaustion during pathogenic insult, heterogeneity in metabolic activity, gene expression patterns, and responsiveness to cytokines such as interferons (IFN) have been revealed. Yet, how this diversity in the system is generated and maintained remains poorly understood. Here, we show that intra-cell type heterogeneity in expression of IFN-stimulated genes (ISGs) is already established at the level of the hematopoietic stem cell (HSC). Transplantation experiments using different reporter mouse models indicated stable inheritance of the ISG expression to downstream progeny. Single cell transplantation experiments of wild type (WT) HSCs supported these findings, proposing a stable inheritance of IFN signaling heterogeneity from HSCs to mature blood cells. Next, we investigated the origin of ISG heterogeneity. From a first streak of primitive hematopoiesis early in embryonal development to the expansion of definitive HSCs in the fetal liver, HSCs pass through a number of embryonal sites. Fetal liver HSCs at E13.5 already showed ISG expression heterogeneity, comparable to the adult stem cells. Yet, at earlier time points during development the degree of ISG expression was depending on the time point and organ the cells were isolated from. In both WT and reporter mice the highest degree of ISG expression was found in the placenta. These data suggest an important role for the placenta during establishment of the heterogeneity. Thus, our data suggest that heterogeneity of IFN signaling in the hematopoietic system, stably inherited from stem cells to progeny, is already established early during hematopoietic development. Uncovering the origin and function of the heterogeneity will have far-reaching implications for HSC biology in health, disease, and upon infection.