EPO-mediated expansion of late-stage erythroid progenitors in the bone marrow initiates recovery from sublethal radiation stress

Abstract

Erythropoiesis is a robust process of cellular expansion and maturation occurring in murine bone marrow and spleen. We previously determined that sublethal irradiation, unlike bleeding or hemolysis, depletes almost all marrow and splenic erythroblasts but leaves peripheral erythrocytes intact. To better understand the erythroid stress response, we analyzed progenitor, precursor, and peripheral blood compartments of mice post-4 Gy total body irradiation. Erythroid recovery initiates with rapid expansion of latestage erythroid progenitors-day 3 burstforming units and colony-forming units, associated with markedly increased plasma erythropoietin (EPO). Although initial expansion of late-stage erythroid progenitors is dependent on EPO, this cellular compartment becomes sharply down-regulated despite elevated EPO levels. Loss of EPO-responsive progenitors is associated temporally with a wave of maturing erythroid precursors in marrow and with emergence of circulating erythroid progenitors and subsequent reestablishment of splenic erythropoiesis. These circulating progenitors selectively engraft and mature in irradiated spleen after short-term transplantation, supporting the concept that bone marrow erythroid progenitors migrate to spleen. We conclude that sublethal radiation is a unique model of endogenous stress erythropoiesis, with specific injury to the extravascular erythron, expansion and maturation of EPO-responsive late-stage progenitors exclusively in marrow, and subsequent reseeding of extramedullary sites. (Blood. 2012;120(12):2501-2511) IntroductionErythropoiesis is a process of rapid cellular expansion and maturation that maintains the circulating red cell mass under steady-state conditions and in response to anemia. Anemia is a common side effect of radiation treatment, suggesting that the erythroid lineage is a highly sensitive target of ionizing radiation. It is known that circulating reticulocytes are severely depleted after sublethal total body irradiation (TBI) in mice. 1,2 In addition, several studies have suggested that bone marrow progenitors and precursors are directly injured after radiation damage. 3-7 Furthermore, we recently found that 4 Gy TBI rapidly induces the apoptosis of bone marrow erythroid progenitors and precursors, leading to severe depletion of bone marrow erythroblasts. 8 Thus, radiation-induced erythroid stress, in which marrow erythroblasts are directly depleted and peripheral red cells relatively preserved, is nearly the opposite of more traditional erythroid stressors, such as bleeding or hemolysis in which the circulating red cell compartment is rapidly and severely lost but bone marrow erythroblasts are preserved.Erythropoietin (EPO) is the central cytokine regulator of the erythroid lineage. The majority of steady-state erythropoiesis occurs in the bone marrow and is regulated by EPO-mediated survival and proliferation of late-stage erythroid progenitors and immature precursors. 9-11 After pathologic damage that threatens oxygen tension, such as the acute loss of red bloo...

The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis

“…1SA). In fact, mouse spleen is a key site for extramedullary erythropoiesis in response to either stress erythropoiesis (4,42). No significant differences in the process of terminal erythroid differentiation between control and Prx2 -/-bone marrow were evident ( Fig 1B).…”

Ontogeny of erythroid gene expression

“…In fact, we have found that after genotoxic injury, a wave of proerythroblasts within the murine BM transition to orthochromatic erythroblasts in just 48 hours. 43 A set of several thousand core erythroid genes composed of tissue-restricted transcripts are expressed in the primitive, fetal definitive, and adult definitive erythroid lineages. Surprisingly, we found no evidence that these transcripts were preferentially retained compared with non-tissue-restricted or housekeeping genes during the terminal stages of erythroid maturation.…”

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…82,83 Increased Epo levels are associated with further induction of BclxL and suppression of Bim and Fas-FasL, with a net increase in the number of erythoid progenitors surviving and proliferating. 82,83 In addition, the downstream transcription factor Stat5 can increase erythoid iron intake through Irp2-mediated increased Tfr1 translation. In SE, however, additional proteins and mechanisms are required that do not seem to be essential to steady-state erythropoiesis.…”