Mechanisms of somatic mutations in HSCs during hematological stresses
Previous and Current Research
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.
Future Projects and Goals
HSCs change their behavior upon aging. Their functionality is gradually declined, which refers to the exhaustion of stem cells, and they become more quiescent, increase the rate of self-renewal divisions, have impaired DNA damage response, less competitive upon transplantation with young HSCs, reduce the production of red blood cells and lymphocytes (especially B cells) and a relative increase in the production of myeloid cells and platelets. Therefore, the functional decline of aged HSCs may be a consequence of the imbalance between self-renewal and differentiation. This again can be a reason for the increased frequency of malignant disorders of the hematopoietic system upon senescence. We aim to understand the mechanism of HSCs senescence and find the approaches for HSCs rejuvenation.
Accumulation of somatic mutations and genome defects in hematopoietic stem cells and progenitor cells is a common cause for adult cancers such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Therefore, we are interested in the mechanisms driving the accumulation of somatic mutations in HSCs, which lead to hematopoietic malignancies.
Methodological and Technical Expertise
- Transplantation of hematopoietic stem and progenitor cells in mice, including single cell transplantation
- Flow cytometry
- 3D bone marrow imaging
- Hematopoietic stem and progenitors in vitro and in vivo analyses
Ramasz B, Krüger A, Reinhardt J, Sinha A, Gerlach M, Gerbaulet A, Reinhardt S, Dahl A, Chavakis T, Wielockx B, Grinenko T
Hematopoietic stem cell response to acute thrombocytopenia requires signaling through distinct receptor tyrosine kinases.
Blood 134 (13):1046–1058 (2019)
Grinenko T, Eugster A, Thielecke L, Ramasz B, Krüger A, Dietz S, Glauche I, Gerbaulet A, von Bonin M, Basak O, Clevers H, Chavakis T, Wielockx B
Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice.
Nat Commun.15;9(1):1898 (2018)
Singh RP*, Grinenko T*, Ramasz B, Franke K, Lesche M, Dahl A, Gassmann M, Chavakis T, Henry I, Wielockx B
Hematopoietic Stem Cells but Not Multipotent Progenitors Drive Erythropoiesis during Chronic Erythroid Stress in EPO Transgenic Mice.
Stem Cell Reports 10(6):1908–1919 (2018) (*equally contributed as first authors)
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Grinenko T, Arndt K, Portz M, Mende N, Günther M, Cosgun KN, Alexopoulou D, Lakshmanaperumal N, Henry I, Dahl A, Waskow C
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