Dresden International Graduate School for Biomedicine and Bioengineering

Hematopoietic stem cells (HSCs) are a rare multipotent cell population that resides at the top of the hematopoietic tree. While most adult HSCs normally exist in a quiescent state, a fraction of them divides and support the production of all mature blood cell types through multiple intermediate progenitor stages. The delicate coordination between differentiation and proliferation of these cells ultimately regulates the maintenance of the entire hematopoietic system. Dysregulation of the differentiation process can lead to malignant transformation or insufficient haematopoiesis, therefore the understanding of HSCs fate decision regulations is crucially important. Previously, we have studded how cell cycle progression and HSCs fate decisions are connected. We revealed that in vivo, HSCs are able to differentiate into restricted progenitors before cell division; a decision they can take already in the G0/G1 phase of the cell cycle. Therefore, some unknown mechanisms, which are connected with cell cycle progression, regulate HSCs fate decisions.

While most adult HSCs normally rarely divided cells, they rapidly enter the cell cycle and differentiate in response to infection or injury. We have found that HSCs start to proliferate in response to chronic high erythropoietin level and acute thrombocytopenia (model of autoimmune thrombocytopenic purpura). Maintenance and activation of HSCs are tightly regulated by both cell-intrinsic (transcription, epigenetics, and metabolism) and cell extrinsic mechanisms (fluid factors or cell-cell interaction provided by bone marrow microenvironment, so-called ‘niche’). We have shown that BM niche cells (megakaryocytes) regulate the activation of HSCs through direct cell-cell interaction. We could also show that hematopoietic stem and progenitors cells need to get two signals in order to be activated in response to specific hematopoietic stress.