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13 Hematopoietic Stem Cells: Molecular Diversification and Developmental Interrelationships

Stuart H. Orkin


Blood cells are continuously produced throughout our lifetime from rare pluripotent bone marrow stem cells, called hematopoietic stem cells (HSCs). HSCs are endowed with two characteristics: They give rise to additional HSCs through self-renewal and also undergo differentiation to progenitor cells that become variously committed to different hematopoietic lineages (Weissman 2000). Operationally, HSCs are best described as those cells capable of reconstituting the hematopoietic system of a recipient individual. Indeed, this defining in vivo property forms the basis of bone marrow transplantation, which was first developed as a lifesaving clinical procedure nearly a half century ago.

Despite the recognition decades ago that HSCs exist, many questions regarding their origins, regulation, and developmental potential remain unresolved. These include (1) How are HSCs formed during development? (2) How do they choose between a resting state and self-renewal/differentiation? (3) How is the remarkable diversity of blood cells (red cells, white cells [neutrophils and monocytes/macrophages], T- and B-lymphocytes, megakaryocytes, mast cells, eosinophils) established at the molecular level? (4) How can our prior views and understanding of HSCs be reconciled with recent findings of unsuspected plasticity of HSCs and other somatic cells?

Characterization of HSCs by their function, that is, by their capacity to sustain long-term multilineage hematopoiesis in a recipient individual, has provided an assay system for cell populations separated by cell-surface markers defined by monoclonal antibodies to surface molecules. In general, the bone marrow of adult animals, most often mice, has been used as the source of potential...

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