TY - JOUR
T1 - Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation
AU - Chen, Yuanting
AU - Xiang, Jie
AU - Qian, Fenghua
AU - Diwakar, Bastihalli T.
AU - Ruan, Baiye
AU - Hao, Siyang
AU - Sandeep Prabhu, K.
AU - Paulson, Robert F.
N1 - Funding Information:
This work was supported, in part, by grants R01 DK080040 (R.F.P) and R01 DK077152 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, and by the Office of Dietary Supplements (K.S.P.) and US Department of Agriculture–National Institute of Food and Agriculture Hatch project numbers PEN04581 (Accession No. 1005468) (R.F.P.) and PEN04605 (Accession No. 1010021) (K.S.P.).
Funding Information:
This work was supported, in part, by grants R01 DK080040 (R.F.P) and R01 DK077152 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, and by the Office of Dietary Supplements (K.S.P.) and US Department of Agriculture-National Institute of Food and Agriculture Hatch project numbers PEN04581 (Accession No. 1005468) (R.F.P.) and PEN04605 (Accession No. 1010021) (K.S.P.).
Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.
PY - 2020/7/9
Y1 - 2020/7/9
N2 - Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor g (PPARg)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.
AB - Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor g (PPARg)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.
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U2 - 10.1182/blood.2019003480
DO - 10.1182/blood.2019003480
M3 - Article
C2 - 32350523
AN - SCOPUS:85087816963
SN - 0006-4971
VL - 136
SP - 235
EP - 246
JO - Blood
JF - Blood
IS - 2
ER -