Regeneration in Hematopoiesis
Previous and Current Research
Immune cells are descendants of bone marrow-resident hematopoietic stem cells (HSC) and are regenerated throughout life, thus, they have the unique capability to continuously regenerate but also to give rise to non-self renewing multipotent progenitor cells. Regeneration of HSC can be shown by serial transplantation into irradiated recipient mice. We recently developed a mouse strain, which can be easily reconstituted without previous conditioning (irradiation or treatment with cytotoxic drugs) and we therewith defined all parameters involved in successful HSC transplantation. We will now use this tool to study regulatory mechanisms involved in HSC maintenance.
Dendritic cells (DCs) are important regulators of immune responses. Depending on their state of activation they can either induce immunity or tolerance. We have shown that DCs are short-lived and that they are continuously replenished from blood-borne progenitors, which have a strikingly low residence time during their transition through peripheral blood. Differentiation into distinct cell lineages is currently understood as a gradual loss of developmental potential. Identification of several lineage-committed progenitor populations in the bone marrow or spleen supports this model. Lineage-restricted progenitors are identifiable by expression of distinct combinations of cell surface markers. We performed gene expression profiling of DC-committed progenitor cells and now aim at understanding the molecular mechanisms underlying DC-lineage differentiation on a candidate-based approach.
Furthermore we will assess growth factor receptor requirements for the development of DC in vivo. To this end we will combine growth factor receptor mutants involved in DC generation aiming at generating a mouse mutant devoid of DC.
Future Projects and Goals
Understanding the principles of continuous regeneration and cell differentiation is a prerequisite to modulate hematopoiesis. The lab will be focused on the identification of cellular and molecular events regulating hematopoietic cell fate decisions with emphasis on DC development.
- Characterization of cellular and molecular pathways involved in HSC maintenance.
- Characterization of molecular pathways involved in DC cell generation.
- Identification of growth factor receptor requirements for the development of DC in vivo.
Methodological and Technical Expertise
- flow cytometry including phosflow
- mouse experiments (transplantations, surgery, humanization)
Cosgun* KN, Rahmig* S, Mende N, Reinke S, Hauber I, Schäfer C, Petzold A, Weisbach H, Heidkamp G, Purbojo A, Cesnjevar R, Platz A, Bornhäuser M, Schmitz M, Dudziak D, Hauber J, Kirberg J, Waskow C
Kit Regulates HSC Engraftment across the Human-Mouse Species Barrier.
Cell Stem Cell, in press, dx.doi.org/10.1016/j.stem.2014.06.001 (2014)
Grinenko T, Arndt K, Portz M, Mende N, Günther M, Cosgun KN, Alexopoulou D, Lakshmanaperumal N, Henry I, Dahl A, Waskow C
Clonal expansion capacity defines two consecutive developmental stages of long-term hematopoietic stem cells.
J Exp Med. 211:209–215 (2014)
Arndt K, Grinenko T, Mende N, Reichert D, Portz M, Ripich T, Carmeliet P, Corbeil D, Waskow C.
CD133 is a modifier of hematopoietic progenitor frequencies but is dispensable for the maintenance of mouse hematopoietic stem cells.
Proc Natl Acad Sci U S A. 110:5582–5587 (2013)
Waskow C, Madan V, Bartels S, Costa C, Blasig R, and Rodewald HR.
Hematopoietic stem cell transplantation without irradiation.
Nat Methods. 6:267–9 (2009)