Extrinsic regulation of the self-renewal process of hematopoietic stem cells

Background: Stem cells play an important role in modern medicine because of their involvement in disease development and propagation (e.g. cancer stem cells) as well as their therapeutic potential (e.g. hematopoietic stem cell transplantation). The commonality of all stem cells is their ability to self-renew, which means that after each cell division, at least one daughter cell is identical to its mother cell. This process is dependent on a specific micro- environment - the so called stem cell niche. Despite decades of intense research only little progress has been made in truly understanding the self-renewal process and the necessary external signals that facilitate it. Objectives: The objective of the suggested project is to identify molecules and/or cytokines that govern the self- renewal process of mouse hematopoietic stem cells (HSCs). Methods: This project is based on 5 years of research on the isolation and identification of mouse HSCs and the biological influence of micro-environmental factors on them. Based on newly developed isolation techniques, HSCs can be isolated to near purity (1 out of 2 cells is actually a HSC), which allows performing experiments with unparalleled exactitude. Furthermore, the newly developed culture system based on stromal cell conditioned medium allows the investigation of quiescent and cycling HSCs ex vivo. Both techniques enable researchers to investigate the self-renewal process with unprecedented clarity. Based on high throughput gene expression analyses, molecules and cytokines that influence the self-renewal process will be identified and tested for their biological effects in vitro as well as in vivo. Expected Outcomes: Greater understanding of the self-renewal process and the identification of possible intervention points will result from this project.