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Stadt Ulm, Deutschland

Spokesperson

Prof. Dr. Karin Scharffetter-Kochanek
Klinik für Dermatologie und Allergologie
Albert-Einstein-Allee 23
89081 Ulm


Head

Prof. Dr. Hartmut Geiger
Klinik für Dermatologie und Allergologie
Universität Ulm
James Franck-Ring 11c
89081 Ulm


Project 9

Changes in the interaction of aged hematopoietic stem cells with the bone marrow niche/stroma: Influence of stem cell aging

Stem cell function decreases with age in mice as well as in humans. We were able to link this functional loss with aging-associated reduced tissue regeneration and impaired tissue repair following injury. Hematopoietic stem cells (HSCs) from older animals have a reduced self-renewal capacity. Similarly, their ability to efficiently carry out hematopoiesis and erythroid and lymphoid differentiation is impaired. The differences in HSC function between young and old animals are largely intrinsic with regard to the stem cell.

HSCs reside in specialized, three-dimensional microenvironments, or niches, in the bone marrow (BM). The endosteal niche is localized in the endosteal section of the bone and is comprised of stromal cells as well as extracellular matrix molecules. It is thought that adhesive cell-cell interactions between HSCs and stromal cells in the endosteal niche regulate HSC proliferation and differentiation. Thus, interactions between HSCs and stromal cells in the niche are essential for HSCs.

Members of the small RhoGTPases control the actin cytoskeleton, as well as signal transduction and gene expression in hematopoietic cells. Our previous work demonstrated that HSCs from older animals, in contrast to cells from younger animals, adhere less efficiently to stromal cells. Additionally, expression of adhesion molecules differs between young and old HSCs. Systematic application of the cytokine granulocyte colony stimulating-factor (G-CSF) induces HSC mobilization from BM into the peripheral blood (PB). Mobilization of HSCs requires their release from the niche/stroma. In accord with the reduced adhesion of old HSCs to stroma, we demonstrated that HSCs in older animals were easier to mobilize. This phenotype, which is specific for older animals, correlates with increased activity of the small RhoGTPase Cdc42.

Therefore, we propose a new concept with the main hypothesis that the interactions (localization/migration/adhesion/spacing) as well as polarization of old HSCs in relation to the stroma/niche are qualitatively and quantitatively different from those of young HSCs, and that these differences are at least partially due to the increased activity of the small RhoGTPase Cdc42 in older HSCs. Our analyses have concentrated on 1) investigation of adhesion of old HSCs to stromal cells, 2) determination of the role Cdc42 performs in stem cell aging, and 3) determination of the role of reactive oxygen species in these processes. A better understanding of these processes will lay the foundation for the potential to be able to modify old HSCs, and may also be used to discover new therapeutic approaches to improve the reduced hematopoiesis that commonly afflicts the elderly.

Chief Investigator

Prof. Dr. Harmut Geiger
Clinic for Dermatology and Allergic Diseases
University of Ulm
Life Science Building, N27
James-Franck-Ring
89081 Ulm
Germany

Phone: +49 (0)731 500 57650
Fax: +49 (0)731 500 57651
hartmut.geiger[at]uni-ulm.de

References

List of publications from:
Hartmut Geiger
>> Pubmed


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