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 5

Population I cells can provide erythroid short-term radio protection when transplanted into secondary recipients.

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Population I cells can provide erythroid short-term radio protection whe...
(A) Population I and II cells isolated by FACS from the spleens of CD45.1 mice transplanted with 5 × 105 control (CD45.2+) bone marrow cells on day 8 after transplant were transplanted into lethally irradiated CD45.1 secondary recipients. The secondary transplants were analyzed for survival (B), hematocrit recovery (C), reticulocyte generation (D), rbc count (E), hemoglobin (F), platelet count (G), and wbc count (H) in Population I and II secondary transplants. The values for the recovery of mice transplanted with unfractionated bone marrow transplants and control untreated mice are indicated. (I) Flow cytometry analysis of peripheral blood mononuclear cells. Cells were harvested 42 days after secondary transplant and stained with anti-CD45.2 and the indicated antibodies (top) or isotype controls (bottom). Data are representative of 3 mice. (J) Analysis of Hbb alleles on cellulose acetate gels. Secondary transplants (>48 days after transplant) were treated with PHZ to induce anemia. Hbb alleles were tested 7 days later (1st PHZ). The mice were allowed to recover 52 days, then were treated a second time with PHZ, and Hbb alleles were analyzed 7 days later (2nd PHZ). (K). Donor-derived cells were sorted from the spleen or bone marrow of secondary recipients. The cells were plated in “complete” methylcellulose media containing SCF+IL-3+IL-6+ Epo. Colonies were counted and scored as BFU-E or “other” myeloid colonies.