Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling

The production of mature cells necessi- tates that lineage-committed progenitor cells be constantly generated from multi- potential progenitors. In addition, the abil- ity to respond rapidly to physiologic stresses requires that the signals that regulate the maintenance of progenitor populations be coordinated with the sig- nals that promote differentiation of pro- genitors. Here we examine the signals that are necessary for the maintenance of the BMP4-dependent stress erythropoi- esis pathway. Our previous work demon- strated that BMP4, stem cell factor, and hypoxia act in concert to promote the expansion of a specialized population of stress erythroid progenitors in the spleen during the recovery from acute anemia. Our analysis shows that acute anemia leads to an almost complete mobilization of BMP4-responsive stress erythroid burst-forming units; therefore, new stress progenitors must be recruited to the spleen to replenish this system. We show that bone marrow cells can home to the spleen and, in response to a signal in the spleen microenvironment, Hedgehog, they develop into BMP4-responsive stress progenitors. Hedgehog induces the ex- pression of BMP4, and together these 2 signals are required for the development of BMP4-responsive stress progenitors. These data demonstrate that the interplay between these 2 signals is crucial for maintenance of this stress response path- way.