title: PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Hsiang-Ying
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: M Inmaculada
authors.initials: MI
authors.lastname: Barrasa
authors.affiliation: Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Elmes
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D000208:Acute Disease; D000740:Anemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000743:Anemia, Hemolytic / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D051379:Mice; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D010659:Phenylhydrazines / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002087:Butyrates; D002843:Chromatin; C453899:GW 7647; D005938:Glucocorticoids; D047493:PPAR alpha; D010659:Phenylhydrazines; D010671:Phenylurea Compounds; D011965:Receptors, Glucocorticoid; C030299:phenylhydrazine; D004921:Erythropoietin; D011345:Fenofibrate