Stem cells are unique because they have the ability to balance self-renewal with commitment; however, the signals that control this are not fully understood. I think this paper is highly cited because we show how distinct signals interact to control stem cell maintenance. Specifically we show that Notch signaling is highly active in hematopoietic stem cells (HSCs), and is critical for maintaining their undifferentiated state. In contrast, Wnt signaling appears to predominantly control proliferation and survival of HSCs. These data suggest that Notch signaling acts as a switch between renewal and commitment, and provide a model for how Notch and Wnt may be integrated by HSCs to maintain the stem cell state.

This work describes a discovery about the mechanisms that control stem cell function. While self-renewal is now beginning to be understood at a molecular level, what remains unclear is how its individual elements (i.e., proliferation and inhibition of differentiation) are regulated. Our work suggests that these two events can be uncoupled and that Notch and Wnt play complementary roles in stem cell maintenance.

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 through commitment is critical to sustaining life. Our work shows that the balance between HSC self-renewal and commitment is regulated by Notch signaling, and that HSC growth and survival are regulated by Wnt signaling. 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.

  How did you become involved in this research?

In our effort to understand how Wnt signaling exerts its influence on HSCs, we discovered that some transcriptional targets of the Notch pathway were upregulated by Wnt signaling. This got us interested in understanding how Notch and Wnt signaling may be linked in the context of stem cell maintenance. As we followed the Notch pathway to determine how it influenced HSCs, we found that inhibiting the pathway led to increased commitment. This made a prediction that Notch signaling should be active in stem cells and mostly inactive during commitment. Fortunately around this time, we found out that Nick Gaiano at Johns Hopkins had generated a Notch reporter mouse. We set up in collaboration with him and this allowed us to show that Notch signaling was in fact highly enriched in stem cells, and was rapidly shut off as stem cells differentiated. We then went on to define the relative roles of Notch and Wnt signaling in this context and found that Wnt signaling was dominant in influencing growth and survival, and Notch signaling was essential for maintaining the undifferentiated state.