Searching for stem cell regulatory molecules. Some general thoughts and possible approaches.

Hematopoietic development in the mammal can be represented as a numerically expanding hierarchy of cell populations that are progressively restricted in their self-renewal and differentiation abilities. Classical functional studies have now been extended to provide exact physical descriptions of various stages in the hematopoietic hierarchy. In particular, much information is available that defines the properties of the most primitive stem cell compartment. In addition, a number of in vitro culture systems suggest the possibility of maintaining and expanding these cells in a defined context. In all developmental systems, unique profiles of expressed genes define distinct differentiation stages. Within these profiles are gene products that play crucial roles in the regulation of cell-fate decisions. Recent progress in hematopoietic biology provides the framework within which to define molecular phenotypes for hematopoietic stem cells and their immediate clonal progeny. Identifying novel gene products expressed predominantly in uncommitted stem cells together with functional loss and gain-of-function approaches should begin to unravel the molecular mechanisms that govern biological phenomena such as self-renewal, commitment, and proliferation in the hematopoietic system.