Blood, 15 January 2003, Vol. 101, No. 2, pp. 381-382
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.
Tariq Enver
Institute of Cancer Research, Gene Function and Regulation
