%0 Generic
%A Werner, Paula Sophie
%C Heidelberg
%D 2020
%F heidok:28944
%R 10.11588/heidok.00028944
%T Development, Maintenance, and Role of Stem Cell Based Interferon Signaling Heterogeneity in the Hematopoietic System
%U https://archiv.ub.uni-heidelberg.de/volltextserver/28944/
%X Inflammation or infections have 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, differentiation capacity, and responsiveness to cytokines such as interferons (IFN) have been revealed. However, how this diversity in the system is generated and maintained remains poorly understood. In this thesis, I explored three aspects of IFN signaling heterogeneity in the hematopoietic system. First, I investigated the origin of IFN signaling heterogeneity during hematopoietic development (1.). Here, I was able to show that differences in baseline IFN signaling are already present at the onset of definitive hematopoiesis at embryonal day (E) 10.5 of development. In addition, I identified the placenta as an embryonic niche that provides definitive hematopoietic stem cells (HSCs) with stable high basal IFN signaling. Second, I investigated the function of IFN signaling heterogeneity both during embryonic development and in different cell populations of the adult system (2.). I uncovered a potential role for higher baseline IFN signaling in mediating protection against infections and pathogen invasion in hematopoietic cells during development. Furthermore, in the adult my data indicate that T cells with different levels of baseline IFN signaling display different activation efficiencies and expression of immune checkpoint molecules following in vitro stimulation. Thirdly, I investigated the mechanisms of IFN signaling heterogeneity (3.). Analysis of DNA methylation patterns of cells with different levels of basal IFN signaling revealed possible epigenetic differences both during development as well as in the adult hematopoietic system. Understanding the origin, function, and mechanism of IFN signaling heterogeneity during hematopoietic development and in the adult hematopoietic system will allow targeting of specific aspects of the pathway to improve response to infections, inhibit development of infectious diseases and possible hematological malignancies, improve existing treatments or develop new treatment approaches.  In addition to the investigation of IFN signaling heterogeneity in the hematopoietic system, a fourth aim of my PhD thesis concentrated on the role of the extracellular matrix (ECM) in the stress-induced activation of HSCs (4.). Previous studies from our group (Uckelmann et al., 2016) could show that the ECM component Matrilin-4 (Matn4) plays an indispensable direct role in the activation of HSCs upon inflammatory stress. I investigated several other ECM components, but only found minor differences in the hematopoietic compartment of mice lacking these components during homeostasis and under inflammatory stress. However, the ECM is a complex and dynamic network of constantly interacting components and novel approaches will be necessary to understand the two-way communication between HSCs and the ECM under inflammatory stress.