Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors
Omid F. Harandi, … , Daniel Mckeone, Robert F. Paulson
Omid F. Harandi, … , Daniel Mckeone, Robert F. Paulson
Published November 8, 2010
Citation Information: J Clin Invest. 2010;120(12):4507-4519. https://doi.org/10.1172/JCI41291.
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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 2

Analysis of stress erythroid progenitor populations by flow cytometry and colony assays.

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Analysis of stress erythroid progenitor populations by flow cytometry an...
Spleen cells were isolated from CD45.1 mice transplanted with mutant (C57BL/6-f/f) or control (C57BL/6) bone marrow cells. (A) Spleen cells from mice transplanted with control bone marrow cells were labeled with anti-Kit, CD71, and Ter119 antibodies, then gated on Kit+ cells. Expression of CD71 and Ter119 was analyzed by flow cytometry. Populations I–III are indicated. (B) Total number of each stress progenitor population in the spleen after transplant. Data represent the average of 3 mice. (C) Enlarged representation of boxed region in B. (D) Total number of Sca1+ cells in the spleen following transplant. (E) Stress erythroid progenitors in the spleens of mice transplanted with mutant or control bone marrow cells after transplant. Cells were analyzed as described in A. (F) Total number of Populations I–III in mice transplanted with mutant or control bone marrow cells. (G–I) BFU-E colony-forming potential of Population I cells (G) and CFU-E colony-forming potential of Population I (H) and Population II (I) cells isolated by FACS from the spleens of mice transplanted with mutant or control bone marrow cells, on day 8 after transplant. Cells were plated in methylcellulose media containing the indicated growth factors and cultured at 20% or 2% O2. For all conditions, control cells produced significantly more BFU-Es or CFU-Es than mutant cells (P < 0.05). *P < 0.05; **P < 0.01; ***P < 0.005. For each time point, at least 3 independent mice were analyzed.