The mechanisms that regulate cell fate decisions during the establishment of the hematopoietic stem and progenitor cell hierarchy are poorly understood. As in all developmental systems, hematopoietic regulation is mediated by cell autonomous (stem and progenitor cell derived) and instructive (microenvironmental) mechanisms. Despite many years of effort in the murine and human systems, the mechanistic features of self-renewal versus commitment decisions, lineage partitioning choices, and other aspects of stem and progenitor cell biology, such as proliferative and migratory phenomena, have remained obscure. Most of the available information has been obtained by studies focused on individual gene-products such as transcriptional regulators and cell surface receptor-ligand pairs. While informative, these studies have not provided systems that permit the ex vivo expansion or directed differentiation of primitive hematopoietic cell populations. We have suggested that the regulation of hematopoietic stem cells should be viewed in a collective, systems biology manner. Thus, the control of cell fate choices is a property of numerous interacting regulatory pathways and networks. In order to set the stage for such a systems biology approach, we have attempted to describe the genetic program or molecular """"""""parts list' characteristic of early stages in the murine hematopoietic cell hierarchy, and of its supportive microenvironmental niches. These global genomic efforts are nearing completion, and have yielded numerous functional insights into stem cell regulation. A key feature of our efforts is the development of web-based interactive databases to facilitate information dissemination within the scientific community. In the present application, we will extend our efforts to the human hematopoietic system, and merge the molecular information obtained in the two species. An emphasis will be placed on identifying regulatory features shared by mouse and man, and on initiating functional genomic studies, with these shared features as a guide. We will continue to employ sophisticated computational strategies in our data analysis, and further develop the databases for the scientific community.
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