It describes the discovery of a signal that regulates hematopoietic stem cell self-renewal. This may have broad implications because it may provide insight into self-renewal of stem cells in other tissues, and may also help explain the uncontrolled self-renewal that occurs in cancer. Additionally, the ability to expand HSCs may have important implications for medicine, because bone marrow transplantation, which is used for treatment of many diseases, is limited by the numbers of HSCs that can be harvested from a given individual. One way to circumvent this problem is to expand HSCs in vitro and then transplant increased cell numbers. Our identification of Wnt as a signal that can enhance self-renewal in murine HSCs raises the possibility that it may promote growth of human HSCs as well, and may be useful in a therapeutic setting.

I became involved in this research as a postdoctoral fellow in Irv Weissman’s lab at Stanford University. The Weissman lab had found that LEF/TCF family transcription factors—which mediate Wnt signaling—were expressed in HSCs, and this led to the idea that Wnt might be important for the growth and maintenance of hematopoietic stem cells. My first observation was that beta-catenin, an intracellular activator of the Wnt pathway, could induce growth of HSCs and maintain them in an undifferentiated state. Later on we wanted to know whether soluble Wnt proteins could do the same thing and if this pathway was required at all by HSCs. Roel Nusse’s lab was across the hall from Irv’s lab, and we started to collaborate on the project with him and his postdoc Karl Willert, who ultimately purified Wnt3A. I moved to Duke in 2001 to start my own lab, and I continued the work here with my student Andrew Duncan, and showed that upstream Wnt signals could also regulate stem cell growth and identified Notch and Hox genes as potential mediators of the effect.

Billions of new blood cells are produced in the body each day, all derived from the hematopoietic stem cell. Because most mature blood stem cells have a limited lifespan, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells for the lifetime of an organism is critical to sustaining life. A key problem in hematopoietic stem cell biology is how HSC self-renewal is regulated. Our work shows that HSC self-renewal is regulated by the Wnt signaling pathway. Progress in the basic understanding of regulation of HSC self-renewal has significant practical ramifications since identification of factors that influence HSC growth is a critical step towards defining ways to expand stem cells in vitro; thereby improving transplantation-based therapies for leukemias and other cancers.