Identifikace a charakterizace nových regulátorů funkce hematopoetických kmenových buněk

Grušanović, Srđan

Hematopoietic stem cells (HSCs) are sitting atop a carefully orchestrated system, called the hematopoietic system. HSCs maintain the constant production of mature blood cells throughout our life, and dysregulated HSC function may lead to severe health problems including bone marrow aplasia and leukemia. Thus, HSC activity needs to be tightly controlled by a complex network of cell intrinsic and cell extrinsic factors. In this thesis, we focus on two previously uncharacterized extrinsic mechanisms that might be involved in the regulation of HSC function. A common aspect of these mechanisms is the production of pro-inflammatory cytokines. First, we investigated the impact of donor NK cells on donor HSC function upon bone marrow transplantation, a frequent clinical intervention. We observed that NK cells negatively affect HSC engraftment and reconstitution during transplantation. To address the potential mechanism, we employed Cebpg knockout mice, which produce non-functional NK cells, and determined that NK cells affect HSC activity through the production of IFNγ. Remarkably, IFNγ-blocking antibodies improved murine and human HSC activity upon bone marrow transplantation. Altogether, we concluded that suppression of inflammatory signals generated by donor innate immune cells can have a significant...

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