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TGF-β inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors

Xiaofei Gao, Hsiang-Ying Lee, Edroaldo Lummertz da Rocha, Cheng Zhang, Yi-Fen Lu, Dandan Li, Yuxiong Feng, Jideofor Ezike, Russell R. Elmes, M. Inmaculada Barrasa, Patrick Cahan, Hu Li, George Q. Daley and Harvey F. Lodish

Key Points

  • The type III TGF-β receptor is a marker that distinguishes “early” and “late” BFU-Es.

  • TGF-β inhibitors increase early BFU-E cell self-renewal and total erythroblast production.

Abstract

Burst-forming unit erythroid progenitors (BFU-Es) are so named based on their ability to generate in methylcellulose culture large colonies of erythroid cells that consist of “bursts” of smaller erythroid colonies derived from the later colony-forming unit erythroid progenitor erythropoietin (Epo)–dependent progenitors. “Early” BFU-E cells forming large BFU-E colonies presumably have higher capacities for self-renewal than do “late” BFU-Es forming small colonies, but the mechanism underlying this heterogeneity remains unknown. We show that the type III transforming growth factor β (TGF-β) receptor (TβRIII) is a marker that distinguishes early and late BFU-Es. Transient elevation of TβRIII expression promotes TGF-β signaling during the early BFU-E to late BFU-E transition. Blocking TGF-β signaling using a receptor kinase inhibitor increases early BFU-E cell self-renewal and total erythroblast production, suggesting the usefulness of this type of drug in treating Epo-unresponsive anemias.

  • Submitted May 22, 2016.
  • Accepted October 7, 2016.
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