From multipotent stem cells, the hematopoietic system undergoes continuous differentiation to generate a remarkable array of mature cells throughout life. These hematopoietic stem cells (HSCs) hold promise for cell therapy through bone marrow transplantation, as well as serving as a paradigm for stem cell biology, so they are the focus of intense investigation. However, studying these cells is impeded by their scarcity—they are present at around 1 per 50,000 bone marrow cells and there is still no reliable method to expand them in vitro.

Gazit et al. analyzed data from hundreds of microarrays to identify sets of genes uniquely expressed in individual hematopoietic cell types. They then mined the HSC-specific gene list to identify candidate markers for HSCs that might be useful to study these rare cells. They found that when mCherry was knocked-in to the locus of one of these genes, Fgd5, red fluorescence could be used to purify virtually all of the HSCs, as rigorously tested by both phenotypic and functional criteria. Moreover, they inserted a tamoxifen-inducible Cre recombinase into the locus, offering the possibility of using this mouse line for HSC-specific deletion or lineage tracing.

There are a number of genes that are highly expressed in HSCs, but most of these are shared with their immediate downstream progeny. Thus, establishing these Fdg5-reporter mouse lines and demonstrating the high and specific expression pattern that can be achieved with insertions into this locus is a significant contribution to the field. The power of the study lies in the utility of the mouse lines, but it also provides a benchmark for such reporters in the future.

This strategy could also be exploited to generate other lineage-specific reporter or deleter mouse lines. The bioinformatics approach generates sets of genes that can serve as what my lab previously termed “cellular fingerprints” that can be used as cell-type identifiers, and some may confer unique cellular properties that merit functional investigation.

Whereas General George S. Patton said, “A pint of sweat saves a gallon of blood,” here we have a valiant effort, undoubtedly representing gallons of sweat, that will be useful for making a pint or more of blood.

et al
J. Exp. Med.