Identification of non-cell-autonomous networks from engineered feeder cells that enhance murine hematopoietic stem cell activity.

In a previous gain-of-function screen, we identified 18 nuclear factors that enhance mouse hematopoietic stem cell (HSC) activity in vitro. Of these factors, the majority was believed to augment HSC function intrinsically. In the current study, we investigated the mechanisms of action of the previously identified agonists of HSC activity and tested whether human HSCs are also responsive to these factors. Our results unexpectedly revealed that the majority of the identified factors confer a competitive advantage to mouse HSCs in a non-cell-autonomous manner. Five of these factors, namely FOS, SPI1, KLF10, TFEC, and PRDM16, show robust transcriptional cross-regulation and are often associated with osteoclastogenesis. These findings define at least one novel non-cell-autonomous network in engineered niches. Surprisingly, and in contrast to their important effect on mouse HSCs, all engineered niches failed to significantly enhance the activity of human HSCs. This last finding further supports a lack of conservation in determinants that control HSC self-renewal in mouse versus human cells.