Publication Date:
2015-05-15
Description:
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 alpha (PPAR-alpha) by the PPAR-alpha 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-alpha agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-alpha alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-alpha co-occupies many chromatin sites with GR; when activated by PPAR-alpha agonists, additional PPAR-alpha is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-alpha agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-alpha agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Hsiang-Ying -- Gao, Xiaofei -- Barrasa, M Inmaculada -- Li, Hu -- Elmes, Russell R -- Peters, Luanne L -- Lodish, Harvey F -- 2 P01 HL032262-25/HL/NHLBI NIH HHS/ -- DK100692/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- R01 DK100692/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Jun 25;522(7557):474-7. doi: 10.1038/nature14326. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA. ; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970251" target="_blank"〉PubMed〈/a〉
Keywords:
Acute Disease
;
Anemia/drug therapy/metabolism/pathology
;
Anemia, Hemolytic/metabolism
;
Animals
;
Butyrates/pharmacology/therapeutic use
;
Cell Culture Techniques
;
Cells, Cultured
;
Chromatin/genetics/metabolism
;
Chronic Disease
;
Disease Models, Animal
;
Erythroid Precursor Cells/*cytology/drug effects/metabolism
;
*Erythropoiesis/drug effects
;
Erythropoietin/pharmacology
;
Female
;
Fenofibrate/pharmacology
;
Glucocorticoids/pharmacology
;
Humans
;
Liver/cytology/drug effects/embryology
;
Mice
;
PPAR alpha/agonists/deficiency/*metabolism
;
Phenylhydrazines/pharmacology
;
Phenylurea Compounds/pharmacology/therapeutic use
;
Receptors, Glucocorticoid/*metabolism
;
Signal Transduction/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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