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

被引:47
作者
Gao, Xiaofei [1 ]
Lee, Hsiang-Ying [1 ]
da Rocha, Edroaldo Lummertz [2 ]
Zhang, Cheng [2 ]
Lu, Yi-Fen [3 ]
Li, Dandan [4 ]
Feng, Yuxiong [1 ]
Ezike, Jideofor [1 ]
Elmes, Russell R. [1 ]
Barrasa, M. Inmaculada [1 ]
Cahan, Patrick [5 ,6 ]
Li, Hu [2 ]
Daley, George Q. [3 ]
Lodish, Harvey F. [1 ,7 ,8 ]
机构
[1] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA
[2] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA
[3] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA
[4] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA
[5] Johns Hopkins Univ, Inst Cell Engn, Baltimore, MD USA
[6] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA
[7] MIT, Dept Biol, Cambridge, MA USA
[8] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA
基金
美国国家卫生研究院;
关键词
HETEROGENEITY; ANEMIA;
D O I
10.1182/blood-2016-05-718320
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 b (TGF-beta) receptor (T beta RIII) is a marker that distinguishes early and late BFU-Es. Transient elevation of T beta RIII expression promotes TGF-beta signaling during the early BFU-E to late BFU-E transition. Blocking TGF-beta 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.
引用
收藏
页码:2637 / 2641
页数:5
相关论文
共 21 条
[1]   GATA Switches as Developmental Drivers [J].
Bresnick, Emery H. ;
Lee, Hsiang-Ying ;
Fujiwara, Tohru ;
Johnson, Kirby D. ;
Keles, Sunduz .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (41) :31087-31093
[2]   Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells [J].
Buettner, Florian ;
Natarajan, Kedar N. ;
Casale, F. Paolo ;
Proserpio, Valentina ;
Scialdone, Antonio ;
Theis, Fabian J. ;
Teichmann, Sarah A. ;
Marioni, John C. ;
Stegie, Oliver .
NATURE BIOTECHNOLOGY, 2015, 33 (02) :155-160
[3]   HIF1α synergizes with glucocorticoids to promote BFU-E progenitor self-renewal [J].
Flygare, Johan ;
Estrada, Violeta Rayon ;
Shin, Chanseok ;
Gupta, Sumeet ;
Lodish, Harvey F. .
BLOOD, 2011, 117 (12) :3435-3444
[4]   Dysregulation of the Transforming Growth Factor β Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia [J].
Ge, Jingping ;
Apicella, Marisa ;
Mills, Jason A. ;
Garcon, Loic ;
French, Deborah L. ;
Weiss, Mitchell J. ;
Bessler, Monica ;
Mason, Philip J. .
PLOS ONE, 2015, 10 (08)
[5]   From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications [J].
Hattangadi, Shilpa M. ;
Wong, Piu ;
Zhang, Lingbo ;
Flygare, Johan ;
Lodish, Harvey F. .
BLOOD, 2011, 118 (24) :6258-6268
[6]   Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway [J].
Herbertz, Stephan ;
Sawyer, J. Scott ;
Stauber, Anja J. ;
Gueorguieva, Ivelina ;
Driscoll, Kyla E. ;
Estrem, Shawn T. ;
Cleverly, Ann L. ;
Desaiah, Durisala ;
Guba, Susan C. ;
Benhadji, Karim A. ;
Slapak, Christopher A. ;
Lahn, Michael M. .
DRUG DESIGN DEVELOPMENT AND THERAPY, 2015, 9 :4479-4499
[7]  
Kaushansky LAM, 2010, WILLIAMS HEMATOLOGY
[8]   TRANSFORMING GROWTH-FACTOR-BETA-1 IS AN INDUCER OF ERYTHROID-DIFFERENTIATION [J].
KRYSTAL, G ;
LAM, V ;
DRAGOWSKA, W ;
TAKAHASHI, C ;
APPEL, J ;
GONTIER, A ;
JENKINS, A ;
LAM, H ;
QUON, L ;
LANSDORP, P .
JOURNAL OF EXPERIMENTAL MEDICINE, 1994, 180 (03) :851-860
[9]   PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal [J].
Lee, Hsiang-Ying ;
Gao, Xiaofei ;
Barrasa, M. Inmaculada ;
Li, Hu ;
Elmes, Russell R. ;
Peters, Luanne L. ;
Lodish, Harvey F. .
NATURE, 2015, 522 (7557) :474-+
[10]   Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E [J].
Li, Jie ;
Hale, John ;
Bhagia, Pooja ;
Xue, Fumin ;
Chen, Lixiang ;
Jaffray, Julie ;
Yan, Hongxia ;
Lane, Joseph ;
Gallagher, Patrick G. ;
Mohandas, Narla ;
Liu, Jing ;
An, Xiuli .
BLOOD, 2014, 124 (24) :3636-3645