The group has a longstanding interest in the development of human hematopoietic cells, both in the bone marrow and in the thymus. Here we focus on the role of extracellular matrix components, their cellular receptors and matrix-degrading proteases. A major topic of our group is the elucidation of the functional role of the bone marrow stem cell niches for healthy hematopoietic stem cells, but also for tumor stem cells which can hijack the stem cell niche(s). The ultimate aim of this research will be the generation of an artificial stem cell niche which will allow us to enrich the number of self-renewing multipotent hematopoietic stem cells.
The hematopoietic stem cell niche: Role of cell-cell and cell-matrix interactions
Stem cell mobilization
The hematopoietic stem cell niche as a primary target for metastatic lesions
T-cell differentiation in the thymus
Prof. Dr. rer. nat Gerd Klein
The human hematopoietic stem cell niche: Role of the extracellular matrix in the human bone marrow.
In the adult organism the development of hematopoietic cells takes place in the bone marrow. Multipotent hematopoietic stem cells which can undergo self-renewal give rise to all the different blood cell types. A specific microenvironment which consists of non-hematopoietic cells, a bunch of secreted and membrane-bound growth factors and a complex extracellular matrix is involved in the differentiation of the stem and progenitor cells. Localized are the stem cells in specific niches. An endosteal niche and a vascular niche have been described, but whether these two niches are different compartments or just the two ends of a continuum is still unresolved. How the two niches differ in their composition of the extracellular matrix and the adhesion receptors is still largely unknown. A major focus of our work is on the characterization of defined extracellular matrix components (e.g., laminin isoforms, tenascin-C, members of the fibulin and netrin families), which play a role in the controlled retention of hematopoietic stem and progenitor cells in the bone marrow, their self-renewal and differentiation.
Bone marrow mesenchymal stem cells
The second adult multipotent stem cells in the bone marrow are mesenchymal stem cells (also called mesenchymal stromal cells, MSC), which are a heterogeneous class of cells. Subpopulations of MSC are also an integral part of the stem cell niches. Using optimal culture conditions MSC can be differentiated into the osteogenic, chondrogenic and adipogenic lineages. The characterization of defined interactions of MSC (subtypes) with hematopoietic stem and progenitor cells is an important topic in our group.
Stem cell mobilization
During cytokine-induced stem cell mobilization altered adhesion mechanisms of hematopoietic stem cells to their niches are highly probable. By treatment with defined cytokines (e.g., G-CSF) an enhanced number of hematopoietic stem and progenitor cells can be mobilized from the bone marrow into the peripheral blood. Our group is interested in how cell adhesion molecules on stem cells and on stromal cells which can mediate cell-cell and cell matrix interactions are influenced by cytokine treatment. There are several strong indications that proteases of different families which can not only digest extracellular matrix, but also cell adhesion molecules and cytokines are mainly involved in the mobilization process (see: Klein et al., Matrix metalloproteinases in stem cell mobilization. Matrix Biol. 2015).
Bone marrow as a primary target for metastatic lesions
In breast and prostate cancer patients, a common tissue for metastatic spread is the skeleton. Probably there are certain aspects of bone physiology which are unique in providing factors for a pre-metastatic microenvironment (the soil in Stephen Paget’s “seed and soil” concept; Paget, 1889) that are conceivably not available (or in reduced amount) in other metastatic sites. Tumor spread, as impressively shown for breast cancer, can be an early event in tumorigenesis. The spreading of the tumor cells is a continuous process which starts with the extravasation from the primary tumor into the circulation (circulating tumor cells: CTCs) which finally can lead to the seeding and engraftment of disseminated tumor cells (DTCs) in pre-metastatic niches. We are interested in the functional interactions of these rare cell populations (CTCs, DTCs) with components of the bone marrow microenvironment.
T-cell differentiation in the thymus
T-cells also develop from hematopoietic stem cells. However, in contrast to all other blood cells, T-lymphocytes develop in the thymus and not in the bone marrow. A specific microenvironment consisting of resident cortical and medullary thymic epithelial cells and a specific extracellular matrix supports the maturation of the T-cells. Adhesion of the maturing T-cells to different laminin isoforms is developmentally regulated. In addition laminin isoforms are essential components of medullary ‘conduits’, an extracellular structure of lymphatic organs whose functions have not yet been resolved.
Prof. Dr. Bernd Rolauffs (Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, University of Freiburg, Germany)
Prof. Dr. Sulev Ingerpuu (Institute of Molecular and Cell Biology, University of Tartu, Estonia)
Prof. Dr. Wolfgang Wagner (Institute for Biomedical Engineering - Cell Biology, RWTH Aachen, Germany)
Dr. Christina Walter, Dr. André Koch, Prof. Dr. Sara Brucker (Department of Obstetrics and Gynecology, University of Tübingen)
Dr. Niklas Harland, PD Dr. Tilman Todenhöfer, Prof. Dr. Willi Aicher (Department of Urology, University Hospital Tübingen
Dr. Hubert Kalbacher (Interfaculty Institute of Biochemistry, University of Tübingen)
SCeNT (Stem Cell Network Tübingen)
Molecular Medicine: “Cell biology I & II”
Immunology: “Introduction to immunology”
Immunology: Seminar “Immunology and stem cell biology” (only during summer semester)
German Research Foundation (DFG)
Wilhelm Sander Stiftung, München
Baden Württemberg Stiftung
Deutsche Krebshilfe Bonn
There are consistently open positions for students of molecular medicine, biochemistry or biology who want to work on their bachelor or master thesis. We are looking for excellent and highly motivated students to join the team. If you are interested in our research, please send us your application by E-Mail. It should include your CV and a cover letter. We are looking forward to your application.
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