Ppar-[alpha] and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

• Autores: Hsiang-Ying Lee, Xiaofei Gao, Inmaculada M. Barrasa, Hu Li, Russell R. Elmes, Luanne L. Peters, Harvey F. Lodish
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 522, Nº 7557, 2015, págs. 474-477
• Idioma: inglés
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• Resumen

  • 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 1,2,3,4,5,6,7,8,9. 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 10,11. 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.