PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal
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Lodish_PPAR-alpha.pdf
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Author(s)
Lee, Hsiang-Ying
Gao, Xiaofei
Barrasa, M. Inmaculada
Li, Hu
Elmes, Russell R.
Peters, Luanne L.
Lodish, Harvey F
Date Issued
May 2015
Journal
Nature
Publisher
Nature Publishing Group
Citation
Lee, Hsiang-Ying et al. “PPAR-α and Glucocorticoid Receptor Synergize to Promote Erythroid Progenitor Self-Renewal.” Nature 522.7557 (2015): 474–477.
Version
Author's final manuscript
Abstract
Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond–Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34+ peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara−/− mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara−/− mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1038/nature14326
