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Centre d'Immunologie et des Maladies Infectieuses
UPMC UMRS CR7 - Inserm U1135 - CNRS ERL 8255

Séminaire du 29/06/17 - Hitoshi Takizawa

13h, Salle 616, Bât "91"

 Hitoshi Takizawa (International Research Center for Medical Sciences, Kumamoto University, Kumamoto, JpN)

Mechanistic insights into the impact of inflammation on hematopoietic stem cell fitness

Invitant : Appay Victor

Lifelong self-renewing hematopoietic stem cells (HSCs) are maintained in quiescence and rarely divide in adult bone marrow (BM), while highly proliferating hematopoietic progenitor (HPCs) are presumably a major contributor for daily hematopoiesis in steady state. In contrast, HSCs can be activated to self-renew or differentiate when hematopoietic need increases upon hematopoietic challenges, such as infection, inflammation. However, it remains poorly understood how most primitive self-renewing translate the demand signal to hematopoietic production and what the biological consequence of HSC activation is on their function.

Here, we study cellular and molecular responses of HSCs toward gram negative bacterial infection, by in vivo challenge of lipopolysaccharide (LPS), a gram-negative bacterial component recognized by Toll-like receptor 4 (TLR4). Repetitive LPS injections activated dormant HSCs to proliferation and differentiation via direct ligation of TLR4. Genetic or pharmacological inhibition of the potential TLR4 downstream signals identified TRIF-Reactive Oxygen Species (ROS)-p38 pathways as the responsible signals for LPS-induced HSC dysfunction. Proliferative stress was accumulated and sustained in HSCs upon LPS and Salmonella infection, via ROS-p38 pathways.

Our findings demonstrate that in vivo administration of LPS directly activates dormant HSCs into proliferation, and compromises their competitive self-renewing and repopulating ability through TLR4-TRIF-ROS-p38-mediated proliferative stress, and point to how chronic inflammation or severe infection might lead to the increased risk for malignant HSC diseases observed in the population-based studies.


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