Previous and current research

Stem cell maintenance is essential for continuous tissue formation and we are generally interested in the process of cell replacement. The constant supply of de novo generated mature cells from adult stem cells is pivotal for the lifelong function of many organs, in particular for tissues with high turn-over rates such as the gut, skin and blood. The ability of a cell to generate offspring with the same developmental potential is called self-renewal, opposing differentiation, where at least one of the progeny has a more limited developmental potential compared to the mother cell. Understanding the mechanisms deciding between self-renewal and differentiation holds the promise of replacement of non-functioning tissues by engineered tissues in the future.

One of the most thoroughly studied adult stem cell is the hematopoietic stem cell (HSC) that gives rise to all types of mature blood cells throughout life, a process called hematopoiesis. HSC can be prospectively isolated to very high purity, however, despite the precise phenotypic description of HSC and more differentiated progenitors, the molecular mechanisms, the involved signals and receptors, participating pathways and their interplay in fate-decision processes of HSC are not resolved. Fate possibilities comprise self-renewal, differentiation, programmed cell death and emigration, and they are clearly regulated by cell intrinsic and extrinsic mechanisms.

HSC give rise to immune cells that are essential for the initiation of immune responses against pathogens, but also for avoiding ‘horror autotoxicus’ (P. Ehrlich), an immune response against self-antigens, which results in destruction of body-intrinsic structures. A specialized immune cell type, the dendritic cell, captures and presents antigens to T cells, and can, in dependence on the maturation of the dendritic cell, activate or inhibit effector cells of the immune system. Therefore, dendritic cells are the main modulators of immune responses and a second focus of the lab is to understand the role of dendritic cell homeostasis and immune regulation.

Normal hematopoiesis is a prerequisite for survival, and failure of hematopoiesis can lead to blood disorders such as anemia, cytopenia or cancer. Thus, tight regulation of hematopoiesis including the choice between self-renewal and differentiation is crucial for the welfare of the organism. Furthermore, most disorders of the blood can exclusively be cured by bone marrow transplantation, replacing the disease-initiating mutant cell with non-mutated cells from a healthy donor. After bone marrow transplantation the infused hematopoietic stem cells disclose their amazing regenerative potential and continuously generate blood cells over long periods of time in the recipient mice.

Fig. 1 Allo- and Xenogeneic transplantation requires conditioning of recipient mice to deplete the endogenous HSC to make ‘space’ for exogenous donor HSC (1) and to reduce the risk of graft rejection (2). We recently developed a mouse mutant that can be transplanted with donor HSC across complete histocompatibility barriers into non-conditioned recipient mice that we use to address novel questions on the biology of HSC.

For these reasons we are interested in understanding the biology of HSC and the microenvironment that supports stem cell growth and fundamental unresolved questions that we work on include:

• How is hematopoiesis controlled on the molecular level?

• What keeps a stem cell a stem cell? / What invites a stem cell to differentiate?

• What is the role of growth factors in lineage choice?

To answer those questions we focus our research on:

• The analysis of mouse HSC on a clonal level

• Improving mouse recipients for the study of the biology of human HSC

• The analysis of human leukemic stem cells – characterization and regulation

• The influence of growth factor receptors on hematopoiesis focusing on dendritic cell development

 

Group Members

List of group members

Selected Publications

C. Waskow, V. Madan, S. Bartels, C. Costa, R. Blasig, H.-R. Rodewald (2009) Hematopoietic stem cell transplantation without irridation. Nature Methods. Nature Methods: Vol 6, 267-26.

C. Waskow, K. Liu, G. Darrasse-Jeze, P. Guermonprez, F. Ginhoux, M. Merad, T. Shengelia, K. Yao, and M. Nussenzweig (2008) The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nature Immunology: 9 (6), 676-683.

K.Liu, C. Waskow, X. Liu, K. Yao, J. Hoh, M. Nussenzweig (2007) Origin of dendritic cells in peripheral lymphoid organs of mice. Nature Immunology: Vol 8 (6), 578-583.

C.Waskow, S. Bartels, S. Schlenner, C. Costa, H.-R. Rodewald (2007) Kit is essential for PMA-inflammation-induced mast-cell accumulation in the skin. Blood: Vol 109 (12), 5363-70.

M.Stumpf, C. Waskow, M. Krötschel, D. van Essen, P. Rodriguez, B. Guyot, R. G. Roeder, T. Borggrefe (2006) The Mediator Complex Functions as a Coactivator for GATA-1 in Erythropoiesis via Subunit Med1/TRAP220. Proc Natl Acad Sci U S A: Vol 103 (49), 18504-9.

G. Terszowski, C. Waskow, P. Conradt, H-R. Rodewald. (2005) Prospective isolation and global gene expression analysis of the colony-forming unit-erythrocyte (CFU-E). Blood: Vol. 105 (5), 1937-1945.

C. Waskow, G. Terszowski,C. Costa, M. Gassmann, H-R. Rodewald. (2004) Rescue of lethal c-Kit(W/W) mice by erythropoietin. Blood: Vol. 104 (6), 1688-1695.

C.Waskow, S. Paul, C. Haller, H. Kissel, P. Besmer, M. Gassmann, H.-R. Rodewald. (2002) A viable c-Kit-deficient (Vickid) mouse mutant reveals pivotal role for c-Kit in maintenance of adult lymphopoiesis. Immunity: Vol. 17, 277-288.

Collaborative Networks:

- DFG Sonderforschungsbereich (SFB) 655, Cells into Tissues

http://www.sfb655.de

http://www.sfb655.de/START/projekte/bereich-b/b9-waskow

- DFG Sonderforschungsbereich (SFB) / Transregio 127, Biology of xenogenic cell and organ transplantation - from bench to bedside

www.sfbtrr127.de

- Seventh Framework Programme (FP7), Advanced Cell-based Therapies for the treatment of Primary ImmunoDeficiency (CELL-PID), Work package 1

http://dev.cell-pid.eu/index.pl

http://dev.cell-pid.eu/index.pl?pos=02.00&lbl=partners

- Dresden International Graduate School for Biomedicine and Bioengineering (DIGS-BB)

http://www.digs-bb.de/digs-bb

http://www.digs-bb.de/digs-bb/research-groups/research-groups/Waskow