Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing

被引:214
作者
Ergen, Aysegul V. [1 ,2 ,3 ]
Boles, Nathan C. [2 ,3 ,4 ]
Goodell, Margaret A. [1 ,2 ,3 ,4 ]
机构
[1] Baylor Coll Med, Interdept Program Dev Biol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Pediat & Stem Cells, Houston, TX 77030 USA
[3] Baylor Coll Med, Regenerat Med Ctr, Houston, TX 77030 USA
[4] Baylor Coll Med, Interdept Program Cell & Mol Biol, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
LIFE-SPAN; REJUVENATION; ACTIVATION; GATA-2; CCL5;
D O I
10.1182/blood-2011-11-391730
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
HSCs undergo dramatic changes with aging. An increase in absolute numbers of HSCs along with a functional deficit in reconstitution potential and a shift toward production of myeloid cells are the hallmarks of murine hematopoietic aging. Here, we show that high levels of the inflammatory cytokine Rantes are found in the aging stem cell milieu. Forced overproduction of Rantes by retroviral expression in BM progenitors resulted in a deficit of T-cell output, and brief ex vivo exposure of HSCs to Rantes resulted in a decrease in T-cell progeny concomitant with an increase in myeloid progenitors. In contrast, Rantes knockout (KO) animals exhibit a decrease in myeloid-biased HSCs and myeloid progenitors and an increase in T cells and lymphoid-biased HSCs. KO HSCs retained their HSC subtype distribution and they produced more lymphoid-biased HSCs in transplantations. Rantes deficiency also resulted in a decreased mammalian target of rapamycin (mTOR) activity in KLS cells. In a heterochronic transplantation setting, we further show that aged HSCs placed in a young environment generate less myeloid cells. These data establish a critical role for environmental factors in the establishment of the aged-associated myeloid skewing phenotype, which may contribute to age-associated immune deficiency. (Blood. 2012; 119(11):2500-2509)
引用
收藏
页码:2500 / 2509
页数:10
相关论文
共 43 条
[1]   Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection [J].
Baldridge, Megan T. ;
King, Katherine Y. ;
Boles, Nathan C. ;
Weksberg, David C. ;
Goodell, Margaret A. .
NATURE, 2010, 465 (7299) :793-U9
[2]   Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion [J].
Beerman, Isabel ;
Bhattacharya, Deepta ;
Zandi, Sasan ;
Sigvardsson, Mikael ;
Weissman, Irving L. ;
Bryder, David ;
Rossi, Derrick J. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (12) :5465-5470
[3]   Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis [J].
Brack, Andrew S. ;
Conboy, Michael J. ;
Roy, Sudeep ;
Lee, Mark ;
Kuo, Calvin J. ;
Keller, Charles ;
Rando, Thomas A. .
SCIENCE, 2007, 317 (5839) :807-810
[4]   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
[5]   Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGF-β1 [J].
Challen, Grant A. ;
Boles, Nathan C. ;
Chambers, Stuart M. ;
Goodell, Margaret A. .
CELL STEM CELL, 2010, 6 (03) :265-278
[6]   Mouse Hematopoietic Stem Cell Identification and Analysis [J].
Challen, Grant A. ;
Boles, Nathan ;
Lin, Karen Kuan-Yin ;
Goodell, Margaret A. .
CYTOMETRY PART A, 2009, 75A (01) :14-24
[7]   Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation [J].
Chambers, Stuart M. ;
Shaw, Chad A. ;
Gatza, Catherine ;
Fisk, C. Joseph ;
Donehower, Lawrence A. ;
Goodell, Margaret A. .
PLOS BIOLOGY, 2007, 5 (08) :1750-1762
[8]   mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells [J].
Chen, Chong ;
Liu, Yu ;
Liu, Yang ;
Zheng, Pan .
SCIENCE SIGNALING, 2009, 2 (98) :ra75
[9]  
Coelho VD, 2010, INT J MED SCI, V7, P1
[10]   Rejuvenation of aged progenitor cells by exposure to a young systemic environment [J].
Conboy, IM ;
Conboy, MJ ;
Wagers, AJ ;
Girma, ER ;
Weissman, IL ;
Rando, TA .
NATURE, 2005, 433 (7027) :760-764