1. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.
- Author
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Lee HY, Gao X, Barrasa MI, Li H, Elmes RR, Peters LL, and Lodish HF
- Subjects
- Acute Disease, Anemia drug therapy, Anemia metabolism, Anemia pathology, Anemia, Hemolytic metabolism, Animals, Butyrates pharmacology, Butyrates therapeutic use, Cell Culture Techniques, Cells, Cultured, Chromatin genetics, Chromatin metabolism, Chronic Disease, Disease Models, Animal, Erythroid Precursor Cells drug effects, Erythroid Precursor Cells metabolism, Erythropoietin pharmacology, Female, Fenofibrate pharmacology, Glucocorticoids pharmacology, Humans, Liver cytology, Liver drug effects, Liver embryology, Mice, PPAR alpha agonists, PPAR alpha deficiency, Phenylhydrazines pharmacology, Phenylurea Compounds pharmacology, Phenylurea Compounds therapeutic use, Signal Transduction drug effects, Erythroid Precursor Cells cytology, Erythropoiesis drug effects, PPAR alpha metabolism, Receptors, Glucocorticoid metabolism
- 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.
- Published
- 2015
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