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 4

Scl and Gata2 expression is regulated by BMP4 during the differentiation of stress erythroid progenitors.

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Scl and Gata2 expression is regulated by BMP4 during the differentiation...
(A) qRT-PCR analysis of Scl (left) and Gata2 (right) expression in Population I progenitor cells sorted from mice transplanted with f/f mutant or control bone marrow on days 6 and 8 after transplant. Expression is relative to Gapdh. (B). Population I stress progenitors were sorted on the indicated days after transplant and incubated alone or with BMP4, Shh, SCF, and hypoxia for 2 hours. Scl (left) and Gata2 (right) expression was determined by qRT-PCR. Expression is relative to Gapdh. (C) Rescue of the f/f defect in stress BFU-E development by retroviral expression of Scl or Gata2. f/f mutant bone marrow cells infected with the indicated viruses were transplanted in mice, and on day 8 after transplant, spleen cells were isolated and plated for stress BFU-Es in methylcellulose media containing either Epo alone or Epo, BMP4, and hypoxia.