Perspectives The hematopoietic stem cell niche in homeostasis and disease

The hematopoietic system requires constant replenishment of its end products, a large and heterogeneous array of terminally differentiated cells and corpuscles, which are essential for oxygenation, clotting, and immunity. Because this daily requirement continues throughout the life of an individual, hematopoietic stem cells (HSCs), the cells at the apex of this well-orchestrated hierarchy, require exceptional control of fate allocation. HSCs are routinely used for clinical applications, as in stem cell transplantation, and represent an important model to study mechanisms of stem cell control. Certainly, stem cell fate decisions are likely to be determined, in part, by cell autonomous signals; however, the inception of the niche hypothesis was motivated by observations that stem cell potential is dependent on microenvironmental clues. Indeed, the initial definition of niche states that “the stem cell is seen in association with other cells which determine its behavior.” Although this definition was conceived to reconcile differences between spleen colony-forming cells and HSCs, the existence of regulatory stem cell nicheswasfirst demonstrated in theDrosophilagonad. Subsequently, niches were found to be critical for adult stem cells in skin, intestine, and brain. The first in vivo proof of microenvironmental regulation of HSCs in mammals used genetically altered murine models, and initiated a series of sophisticated experiments aimed at finding which components of the bone marrow microenvironment regulate HSCs. In this review, we will focus on components of the HSC niche where the concept of heterogeneity underlines the multiple cell fate choices available to the stem cell. We will also discuss how both physiologic and pathologic processes modulate multiple components of the niche, introducing evidence that the microenvironment contributes to the pathophysiology of disease, and conclude by predicting the potential of therapeutic manipulation of the niche.