Long term consequences of immunobiography on HSC’s function and memory – HSC-Immunobiography

Hematopoietic stem cells (HSC) are long-lived cells that allow the regeneration of all blood cells. More and more data allow us to consider HSC as an immune cell. Indeed, they are able to recognize directly certain pathogens or inflammatory cytokines produced at the site of infection. They will respond directly by proliferating and differentiating mainly towards the myeloid lineage and thus filling the deficit of immune cells induced by the infection. Furthermore, we have previously shown that infections induce a stable immune epigenetic memory in HSCs, similar to the one of innate immune cells. This memory allows HSCs to increase their differentiation towards the myeloid lineage upon reinfection.
Because of their long-life span, HSCs will have to respond to numerous infections such as those to which an individual is subjected during his or her life and whose enumeration is called immunobiography. HSCs from chronically infected and aged mice show a similar phenotype such as excessive proliferation and a differentiation bias towards the myeloid lineage leading to a loss of their regenerative function.

Our objective is to evaluate the consequences that multiple infections may have on epigenetic memory and on long-term functions of HSC such as their capacity for self-renewal and differentiation.
To do so, we will:
- Identify inflammatory stimuli that induce epigenetic immune memory in HSCs;
- Test the effect of repeated exposure to these stimuli on epigenetic immune memory and HSCs function;
- Determine whether repeated exposure to these stimuli can lead to uncontrolled immune epigenetic memory and aging of HSCs.

This project will provide a better understanding of epigenetic immune memory in HSCs to explore the benefits and risks that it may induce on long-term HSCs functions. It will also allow to identify new mechanisms of inflammation inducing HSC aging. It is particularly important to understand this mechanism in order to preserve the homeostasis of the hematopoietic and immune systems over time and prevent the development of age-related hematopoietic and immune diseases.