Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors

Abstract

Acute anemic stress induces a systemic response designed to increase oxygen delivery to hypoxic tissues. Increased erythropoiesis is a key component of this response. Recovery from acute anemia relies on stress erythropoiesis, which is distinct from steady-state erythropoiesis. In this study we found that the bone morphogenetic protein 4-dependent (BMP4-dependent) stress erythropoiesis pathway was required and specific for erythroid short-term radioprotection following bone marrow transplantation. BMP4 signaling promoted the development of three populations of stress erythroid progenitors, which expanded in the spleen subsequent to bone marrow transplantation in mice. These progenitors did not correspond to previously identified bone marrow steady-state progenitors. The most immature population of stress progenitors was capable of self renewal while maintaining erythropoiesis without contribution to other lineages when serially transplanted into irradiated secondary and tertiary recipients. These data suggest that during the immediate posttransplant period, the microenvironment of the spleen is altered, which allows donor bone marrow cells to adopt a stress erythropoietic fate and promotes the rapid expansion and differentiation of stress erythroid progenitors. Our results also suggest that stress erythropoiesis may be manipulated through targeting the BMP4 signaling pathway to improve survival after injury.

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

“…50 Thus, we considered the possibility that LDN-193189 acts to increase erythrocyte counts or induce polycythemia via direct effects on the turnover or proliferation of early hematopoietic stem and progenitor cells. Phenotypic analysis of BM cells demonstrated that prolonged administration of LDN-193189 to mice did not elicit changes in early hematopoietic or erythroid progenitor lineages.…”

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.…”

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

“…The ability of BFU-E progenitors to undergo limited self-renewal during stress erythropoiesis allows rescue of lethally irradiated mice from anemia, and retransplantation also protects secondary and tertiary recipients. 84 In this regard, stress erythropoiesis is similar to definitive fetal liver erythropoiesis and Friend virus-induced erythroleukemia, 2 other situations where similar mechanisms induce erythroid progenitors to undergo self-renewal rather than to differentiate. Stress erythropoiesis is regulated by SCF, GCs, BMP4, and Hedgehog signaling in addition to tissue hypoxia…”