Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors
Omid F. Harandi, Shailaja Hedge, Dai-Chen Wu, Daniel Mckeone, Robert F. Paulson
Omid F. Harandi, Shailaja Hedge, Dai-Chen Wu, Daniel Mckeone, Robert F. Paulson
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Research Article Hematology

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 post-transplant 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.

Authors

Omid F. Harandi, Shailaja Hedge, Dai-Chen Wu, Daniel Mckeone, Robert F. Paulson

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Figure 1

Mice transplanted with f mutant bone marrow exhibit a defect in erythroid short-term radioprotection.

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Mice transplanted with f mutant bone marrow exhibit a defect in erythroi...
C57BL/6 mice were irradiated and transplanted with C57BL/6-f/f mutant or C57BL/6 control bone marrow. (A–C) Analysis of mice transplanted with 1 × 105 unfractionated bone marrow cells. (A–C) Survival of mice transplanted with mutant or control bone marrow (A), hematocrit recovery (B), and reticulocyte production (C) following transplant. (D) Analysis of hematocrit recovery in mice transplanted with 5 × 105 unfractionated bone marrow cells. For each figure, each time point represents 4–18 recipients from at least 3 independent experiments. (E) Donor-derived (CD45.2+) spleen cells were isolated by FACS on the indicated days from CD45.1 mice that had been transplanted with 5 × 105 mutant or control bone marrow cells. Cells (2 × 106) were plated in methyl­cellulose media containing Epo only. Stress BFU-Es were scored 5 days later. No colonies were observed prior to day 8 following transplant. ND, not detected. *P < 0.05; **P < 0.01; ***P < 0.005.