Stem cell niches in the bone–bone marrow organ and their significance for hematopoieticand non-hematopoietic cancer

The identity of skeletal progenitors found within the bone marrow stroma (skeletal stem cells, also known as “mesenchymal” stem cells) stands at the heart of contemporary skeletal physiology. Likewise, the functional interaction between bone and hematopoiesis remains at the heart of hematopoietic physiology centuries after the unique relationship between these two systems has been noted. Curiously, the two scientific issues find a common origin in certain historical, seminal experiments conducted in the 1960s1. Downstream of these, important ramifi- cations were generated in both experimental work and concepts: in bone physiology, the quest for the definition of the identity and phenotype of a putative class of self-renewing skeletal progenitors has recently met success2,3; meanwhile a significant distortion of the original concept of a stem cell for skeletal tissues found in the bone mar- row stroma has generated a flurry of activity in different directions, which will not be covered here1. In hematopoi- etic physiology, the role of the bone marrow stroma in providing an instructive environment has become a solidly established concept, downstream of the seminal work of Dexter and coworkers4, as well as of Schofield's classical formulation of the concept of a “niche”5. The nature and mechanisms of this instructive environment has been partly elucidated by the identification of crucial cytokines and chemokines that mediate its functional effects. Yet, important questions have remained unanswered, first and foremost the cellular identity and anatomical location of the “niche” harboring and retaining hematopoietic stem cells. Interest in the “niche” effect has been specifically revived over the past decade by advances made using mouse genetics, in vivo imaging, and refined transplanta- tion systems6. Rapidly, general views of the “niche” identity have been revived, proposed anew, or modified. Meanwhile, as a result of both conceptual advances and availability of novel technologies, the link between the physiological significance of the “niche” and “microenvironment” concepts on the one hand, and diseases on the other, has emerged as a relatively novel area of intensive investigation. As advances in the identification of stromal osteoprogenitors in the human and murine bone marrow have singled out these cells as a significant player in the “niche” effect, the same cells have come to be seen as a significant mediator of mechanisms, natural history, and possibly treatment of diseases that involve bone and hematopoiesis, first and foremost (but by no means ex- clusively) hematopoietic cancer and bone metastasis. The following pages are devoted to an attempt to place some of these advances in perspective.