Meeting the demands of mature blood cells under stress conditions
The hematopoietic system is characterized by its enormous proliferative capacities thereby ensuring maintenance of constant numbers of fully matured blood cells under steady-state conditions. For example, in humans approximately 1011 – 1012 blood cells are produced each day. However, under circumstances of hematopoietic challenges such as bleeding or infection the hematopoietic system is able to massively enhance its cellular throughput. Two prerequisites are crucial for a compensatory response to hematopoietic stress. First, disturbances of the hematopoietic equilibrium need to be rapidly sensed and second, these must be adequately translated into a cascade of events that lead to higher blood cell production and differentiation. We are trying to clarify regulatory mechanisms governing these functional properties. In particular, we are interested in how the highly functionally diverse bone marrow microenvironment is involved in these processes. Elucidation of these regulatory loops not only will help to gain better insight into the complex interplay between hematopoietic stem and progenitor cells and their supportive microenvironment but might eventually lead to identification of new avenues to more efficiently treat infections and/or blood diseases.
Understanding of hematopoietic stem cell dysfunction triggerd by chronic inflammation
Continuous blood cell formation is ensured by highly organized stepwise differentiation of lineage-committed progenitors that arise from self-renewing hematopoietic stem cells (HSCs). During chronic inflammation, e.g., infections, autoimmune diseases, replenishment of mature immune cells is in high demand at the site of reaction, which eventually induces HSC proliferation. Accumulation of divisional history in HSC results in functional impairment that would lead to elimination of dysfunctional clone in physiological conditions. However, given a certain condition that allows those clones to escape from normal regulatory control, it might increase rate of the genetic ablative events that leads to malignant transformation. Our aim is to characterize the molecular and epi-/genetic mechanisms which are responsible for HSC dysfunction during chronic inflammation, and further to study association of HSC cycling history with DNA mutational rate.
The bone marrow niche in health and disease
Self-renewing hematopoietic stem cells (HSC) capable of multilineage differentiation are the common ancestors of all types of blood cells. In order to exert their function, HSCs need to be tightly regulated by both intrinsic as well as extrinsic mechanisms. HSCs are located in the bone marrow in a microenvironment consisting of different types of supportive cells also called the HSC niche. The niche provides these extrinsic factors that are necessary for maintaining HSC functionality. Our goal is to identify those specific factors as well as to better characterize niche cells from which these signals originate. In addition, our work focusses on how the hematopoietic system changes as a consequence of naturally-occuring stress such as infection, bleeding and leukemic transformation and how the microenvironment is involved in the adaptation to this stress.
Hematopoietic stem cell aging
Aging has an impact on function of all tissues and their respective stem cells, including the blood system. Hematopoiesis is an active ongoing process in which bone marrow (BM) resident hematopoietic stem cells (HSCs) continuously replenish all types of mature blood cells, most of them having a short life span. Aging has been shown to profoundly influence HSC function, as BM-homing ability, differentiation and self-renewal capacity. However, it remains unclear how HSC division and fate decision are changed during physiological aging and what determines HSC behaviour at a molecular level. We attempt to gain insight into intrinsic and extrinsic regulatory mechanisms of HSC aging, and search for understanding general rules that govern the aging processes.
Hematologic stem cell expansion in health and disease
Hematopoiesis is hierarchically organised and represents one of the best characterized adult stem cell systems. On top of the hierarchy, hematopoietic stem cells (HSCs) show the distinct features of long-term self-renewal and differentiation into the lineages of the hematopoietic system. While still little is known about the mechanisms that confer self-renewal and expansion of hematopoietic stem cells, hematopoietic stem cell transplantation has been performed since decades whereby a limited number of hematopoietic stem cells is capable in rescuing a patient whose bone marrow has been ablated by chemo- and/or radiotherapy.
As impressive the physiologic capacity of hematopoietic stem cells to expand on demand is, as feared are the devastating consequences of an aberrant regulation of self-renewal and expansion of their malignant counterparts leading to leukemia or myeloproliferative neoplasms (MPN).
In these clonal diseases, the existence of a minor fraction of the neoplastic cells termed leukemia initiating cells or leukemia stem cells has been proposed to propagate disease, being less susceptible to chemotherapy due to escape mechanisms and therefore leading to relapse after chemotherapy.
Within this project we are planning to characterize hematologic stem cell expansion in the mouse model, naturally occurring during embryofetal development and after birth as well as artificially induced by irradiation or chemotherapy. Knowledge gained here should help to decipher mechanisms responsible for human hematologic expansion.
In terms of malignant hematologic expansion leading to leukemia and myeloproliferative neoplasms we are planning to separate fractions of disease initiating cells in acute leukemias and myeloproliferative neoplasms in order to exactly define the disease initiating cells and to characterize their distinctive biological properties that could be selectively targeted in the future.
Establishment of human neoplasia in mice
We recently developed next-generation humanized mice that express multiple human cytokines. Upon demonstration that these mice are more suitable for the development and function of healthy human hematopoiesis, we now are testing the potential of these models to sustain primary human myeloid cell malignancies as e.g. myeoproliferative diseases, chronic myeloid leukemia, and Langerhans cell histiocytosis. Improved modelling will allow both, research on the underlying pathophysiology of such neoplastic diseases and preclinical predictive evaluation of new therapies.
Regulation of dendritic cell homeostasis
Dendritic cells (DC) are the antigen presenting cells that act as pedagogues for the generation of an immune response, which are short lived and need to be continuously replenished by the upstream hematopoietic stem and progenitor cells. FMS like tyrosine kinase 3 (Flt3) is a class III membrane bound tyrosine kinase receptor that has been shown to instruct the differentiation of upstream hematopoietic progenitors towards DC lineage, and is expressed on early hematopoietic progenitors, DC precursors and DCs. However, the regeneration kinetics of DC lineage by respective DC progenitors in the context of Flt3 signalling in steady state and under inflammatory conditions remains to be determined. We try to address this by generating and evaluating genetically engineered in vivo models.