Cellcycle-Regulation of Haematopoetic Stem Cells

Stem cells are characterised through their capability of selfrenewal (symmetric cell division) and to give rise to differentiated daughter cells (asymmetric cell division). These characteristics were demonstrated for the first time in hematopoetic stem cells and the transplantation of these cells is nowadays routinely performed in neoplastic and non-neoplastic diseases. Most of the methods established in hematopoetic stem cell research are now used in the research of organ stem cells as well as tumor stem cells. One of the most exciting topic in stem cell research is certainly the cell cycle regulation of these cells, since most of them are quiescent (G0 phase) in adults. These quiescent cells are functionally inactive and resistant to chemotherapy in the case of tumor stem cells. It is therefore of great interest to get an insight in the cell cycle regulation of these cells to be able to manipulate them in the long run. Recently, a cell cycle shift in the hematopoietic stem cells of mice between the 3rd and 4th week after birth from active to inactive was found in the laboratory of Prof. C. Eaves. This dramatic event in the life of hematopoetic stem cells in a relatively short time period, enables researchers to study fundamental regulation mechanisms of stem cells. The planned project aims to investigate cell cycle regulation in hematopoetic stem cells and consists of three parts: in the first part we plan to demonstrate that the 3-week stem cells are indeed the ancestors of the 4-week stem cells. In the second part we plan to characterize the gene products and pathways of the 3-week HSC which are required to execute the cell cycle shift. In the third part we would try to manipulate the cell cycle and to reverse the developmental switch. If it was possible to elucidate the physiology behind the developmental switch of stem cells from an fetal - to an adult program and possibly to reverse this crucial step, the implications for further research would be tremendous. Especially regeneration medicine and cancer research would move into an entire new area of possibilities for therapeutic intervention. Directed cell cycle modulation would enable researches to switch on the silent cancer stem cells which would make them susceptible to chemotherapy and to switch on silent organ stem cells which could rebuild parts or even the whole organ.