Recent advances in understanding extrinsic control of hematopoietic stem cell fate.

Hematopoietic stem cells are responsible for generating all types of blood cells. As such they are under a high degree of regulation, both internal and external. With the identification of the hematopoietic stem cell niche, there has been increased investigation into extrinsic regulation of hematopoietic stem cells with emphasis on developmental signaling pathways. The purpose of this review is to discuss recent advances and findings in how these different pathways interact to achieve a balanced control of these stem cells. Studies indicating the importance of pathways such as Wnt, Notch, bone morphogenic protein, Sonic hedgehog and fibroblast growth factor in controlling the fate of hematopoietic stem cells are the most significant recent findings. These pathways have been implicated to affect various aspects of hematopoietic stem cells, including self-renewal, proliferation and lineage determination. Equally important are studies showing, by inactivation of various pathway components, the complexity of signal integration at the stem cell level in vivo. Additionally, some recent reports have provided evidence for direct interaction or cross-talk between different signaling pathways in this regulation. We review highlights of the recent advances made toward resolving the mechanisms of external regulation of hematopoietic stem cells. Understanding the interaction of different signaling pathways in the context of the hematopoietic stem cell niche is essential for increasing their therapeutic potential.