The mechanisms that regulate the central properties

The mechanisms that regulate the central properties of HSCs are not fully understood. Using the vast resource of ImmGen, we sought to identify genes with enriched HZ-1157 in HSCs, reasoning that such genes might represent key regulators of stem cell fate and function. In support of this, we readily identified several known HSC regulators, including HoxB4, Erg, HoxA9, Meis1, Egr1, and Mecom (Orkin and Zon, 2008), as well as genes that have not previously been implicated in HSC biology. Based on its HSC-specific expression and predicted regulatory role as determined by module analysis, we identified Hlf as a high-priority candidate for functional validation. We found that Hlf endowed HSCs and downstream progenitors with enhanced self-renewal, and sustained long-term mixed myeloid lineage potential during ex vivo culturing. Interestingly, these results complement and extend a previous report examining HLF-expression in human HSPCs, in which ectopic expression of HLF led to an increase in the short-term xenograft potential of human lineage-negative cord blood cells containing HSCs and all of their downstream progenitor progeny (Shojaei et al., 2005). Our finding that HLF can impart potent and sustained self-renewal activity to HSPCs ex vivo suggests that increased self-renewal of HSPCs may underlie the observations reported by Shojaei et al. (2005). The insights this study provides into the transcriptional regulation of HSCs, combined with the identification of HSC-specific transcription factors, could eventually lead to the development of combinatorial strategies aimed at inducing HSC potential in nonstem cells in a manner similar to that used for the reprogramming of other cell types (Graf and Enver, 2009). Moreover, our findings regarding the transcriptional programs that regulate the central properties of HSCs not only provide insights into the basic biology of these cells but may also illuminate innovative strategies to improve their clinical utility.
Experimental Procedures
Acknowledgments