By Mario Marcondes, MD, and Bart Scott, MD

2008-12-09

Hematopoietic stem cells (HSCs) were postulated to exist more than 100 years ago. Experimental verification of their existence in mice was provided by Drs. James Till and Ernest McCulloch in 1961, and the clinical use of HSCs was pioneered by E. Donnall Thomas in the late 1960s. The concept of a regulatory environment determining stem cell fate choices was initially proposed in the 1970s, when R. Schofield hypothesized a structure that housed stem cells and provided regulation of self-renewal and proliferation, since transplantation of HSCs into recipient animals resulted in only limited HSC expansion. In addition to their role in the cure of a variety of malignancies, severe autoimmune disorders, and states of marrow failure, experimental studies of HSCs have served as the road map for our understanding of stem cell development in all of mammalian biology. The transcription factors and growth-promoting cytokines required for stem cell self-renewal and expansion were first identified in HSCs. The notion of stem cell trafficking and migration and the molecular bases for these properties were first determined for HSCs. And the concept of a nurturing microenvironment that provides critical survival and quiescence signals and governs the total body levels of stem cells has been best evaluated for the marrow stem cell niche. While data have recently been collected defining the HSC niche in murine models, its human counterpart had not yet been fully explored. Ongoing studies are now necessary to fully elucidate the existence and characteristics of the human HSC niche.

Today’s Presidential Symposium will bring together three eminent biomedical scientists who have made landmark contributions to our understanding of HSC biology. Dr. Stuart Orkin will address determinant markers of “stem-ness,” the properties that allow for self-renewal and expansion and that govern the fate of stem cells once they begin to differentiate into the formed elements of the blood. He will report findings in which his group targeted the lineage commitment and hierarchy of progenitors that become progressively restricted to several or single cell lineages. Dr. Amy Wagers will then discuss the cellular and molecular bases for stem cell migration, comparing the process for HSCs with that of other organs. Finally, Dr. Francoise Dieterlen-Lièvre will discuss the HSC niche, focusing our attention on the cellular anatomy, the changing sites of hematopoiesis during development, and the cell surface molecules and soluble growth factors that contribute to HSC survival, proliferation, and differentiation. Understanding the components and regulation of the HSC niche will lead to specific manipulation for therapeutic purposes. The cellular components, adhesion molecules, and signaling pathways could potentially serve as targets for modifying the bone marrow microenvironment and the corresponding biologic activity of HSC within the niche. All three scientists have made significant contributions to the field of HSC research, and we eagerly anticipate a lively presentation regarding the biology of HSCs.

Drs. Marcondes and Scott indicated no relevant conflicts of interest.

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