Blueprints for blood

Hematopoietic stem cells are characterized by their ability to undergo self-renewal and, through differentiation, populate all the different blood lineages throughout the lifetime of an organism. How self-renewal and differentiation are orchestrated at a molecular level remains poorly understood but the mechanisms involved are likely coupled within a set of regulatory rules for the stem cell pool that also include the control of cell proliferation, cell quiescence, and programmed cell death.

Experimental probing of the molecular ground state of hematopoietic stem and progenitor cells at the level of chromatin structure and gene expression suggests that the multipotential ground state is preconfigured to facilitate these cell-fate decisions. Thus it has been argued that under conditions of self-renewal stem cells simultaneously “prime” several different programs of lineage-affiliated gene activity. It is presumed that this hematopoietic noise may be functional and may provide the building blocks of future cell-fate decisions. This model, termed “multilineage priming,” predicts that commitment and differentiation requires not only consolidation of appropriate programs but also repression of programs no longer required for the pathway selected.

In this issue Akashi and colleagues (page 383) describe the global molecular profiles of various classes of highly purified murine stem and progenitor cells using microarray technology. Since the phenotype of any given cell is ultimately the product of the genes it expresses or has expressed during its lifetime, this approach is likely to yield significant insight into the molecular basis of “stemness.” The analysis of hematopoietic stem cells (HSCs), multipotent progenitor cells (MPCs), common myeloid progenitors (CMPs), and common lymphoid progenitors (CLPs), inevitably throws up an overwhelming and seemingly unmanageable amount of data. But the authors have nicely distilled some digestible general principles that both echo and refine earlier ideas about molecular ground states. The data indicate that in addition to priming a battery of hematopoietic genes HSCs also express multiple nonhematopoietic genes, including genes characteristic of neuronal, endothelial, pancreatic, kidney, liver, heart, hair, epithelial, and muscle cell types. Such nonhematopoietic “priming” may provide a molecular explanation for the much touted but as yet controversial phenomenon of stem cell plasticity. This broad base of transcriptional accessibility is sequentially restricted in MPCs that display only hematopoietic priming (myeloid and lymphoid gene expression), through CMPs and CLPs that display myeloid-only and lymphoid-only expression, respectively. A word of caution though: names may in some cases unduly influence our view of lineage restrictions. For example, the discovery that the erythropoietin receptor is expressed on endothelial cells only seemed surprising because its name suggested an erythroid-restricted activity!

The interested reader may wish to compare these data with those presented recently in Science where complementary approaches have been used to determine a molecular signature of stemness (Ramalho-Santos et al, Science. 2002;298:597-600 and Ivanova et al, Science. 2002;298:601-604). All in all, these data provide valuable static snapshots of the transcriptional configurations of different developmentally restricted compartments within the hematopoietic hierarchy. We can now look forward to the next phase of experiments, which presumably will entail a dynamic analysis of cells transiting between these different states.