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

Abstract

The production of mature cells necessitates that lineage-committed progenitor cells be constantly generated from multipotential progenitors. In addition, the ability to respond rapidly to physiologic stresses requires that the signals that regulate the maintenance of progenitor populations be coordinated with the signals that promote differentiation of progenitors. Here we examine the signals that are necessary for the maintenance of the BMP4-dependent stress erythropoiesis pathway. Our previous work demonstrated 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 expression 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 pathway. (Blood. 2009;113:911-918)

From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

“…111,112 For BFU-E cells to be responsive to BMP4, they need to be "primed" with Sonic Hedgehog, a morphogen that is also synthesized and secreted by cells in the spleen microenvironment. 113 BMP4, in turn, activates the transcription factor Smad5 as well as Scl and Gata2, which enhances the probability of BFU-E self-renewal over differentiation (Figure 3). 84,114,115 …”

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

“…Given this, we examined the effect of reducing environmental Hh protein in the spleen on Th2 differentiation of nontransgenic CD4 + cells ex vivo. We used Dhh KO CD4 splenocytes, as Dhh is expressed by spleen stroma (40) and, unlike Shh KO, is not an embryonic-lethal mutation. We cultured Dhh KO and WT cells in Th2 skewing conditions and found that Dhh KO cells upregulate Gata3 less efficiently than do WT cells after stimulation (Fig.…”

Erythroid cells generated in the absence of specific 1-integrin heterodimers accumulate reactive oxygen species at homeostasis and are unable to mount effective antioxidant defenses

“…enzymes and factors involved in anti-oxidant signaling), there is a host of other genetically impaired pathways that compromise terminal erythroid differentiation or influence erythropoietin (Epo)-responses, especially after stress. [15][16][17][18][19][20][21][22] In the great majority of these cases, attempts to compensate for RBC losses lead to an increase in erythropoiesis at early stages (ineffective erythropoiesis) and to splenomegaly in mice.…”

“…During stress, bone morphogenetic protein 4/hedgehog signaling and hypoxia are necessary for expanding a specific subset of progenitors within the murine splenic environment to quickly address stress demands for RBC production. 17,18,20 Since the ability of these special progenitor cells to respond to stress depends on cues from the microenvironment (ME) of the spleen rather than the bone marrow (BM), distinct erythroid cell/ME interactions are apparently at play in the former but not the latter environment under stress. Although the spleen has been recognized as the favored ME for stress response in the mouse, the specific ME/hematopoietic cell interactions responsible for the differences between BM and spleen environment have not been defined.…”