Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice

被引:42
作者
Helgason, CD
Antonchuk, J
Bodner, C
Humphries, RK
机构
[1] British Columbia Canc Agcy, Dept Canc Endocrinol, Vancouver, BC V5Z 1L3, Canada
[2] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada
[3] Univ British Columbia, Fac Med, Dept Surg, Vancouver, BC, Canada
[4] Univ British Columbia, Fac Med, Dept Med, Vancouver, BC, Canada
关键词
D O I
10.1182/blood-2002-12-3939
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
SH2-containing inositol 5-phosphatase (SHIP) is an important negative regulator of cytokine and immune receptor signaling. SHIP-deficient mice have a number of hematopoietic perturbations, including enhanced cytokine responsiveness. Because cytokines play an important role in the maintenance/expansion of the primitive hematopoietic cell pool, we investigated the possibility that SHIP also regulates, the properties of cells in these compartments. Primitive hematopoietic cells were evaluated in SHIP-deficient mice and wild-type littermate controls using the colony-forming unit-spleen (CFU-S) and competitive repopulating unit (CRU) assays for multipotent progenitors and long-term lympho-myeloid repopulating cells, respectively. Absence of SHIP was found to affect homeostasis of CFU-S and CRU compartments. Numbers of primitive cells were increased in extramedullary sites such as the spleen of SHIP-deficient mice, although total body numbers were not significantly changed. In vivo cell cycle status of the CRU compartment was further evaluated using 5-fluorouracil (5-FU). SHIP-deficient CRUs were more sensitive to 5-FU killing, indicating a higher proliferative cell fraction. More strikingly, SHIP was found to regulate the ability of primitive cells to regenerate in vivo, as CRU recovery was approximately 30-fold lower in mice that received transplants of SHIP-deficient cells compared with controls. These results support a major role for SHIP in modulating pathways important in homeostasis and regeneration of hematopoietic stem cells, and emphasize the importance of negative cytokine regulation at the earliest stages of hematopoiesis. (C) 2003 by The American Society of Hematology.
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页码:3541 / 3547
页数:7
相关论文
共 60 条
[1]   The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells [J].
Aman, MJ ;
Lamkin, TD ;
Okada, H ;
Kurosaki, T ;
Ravichandran, KS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (51) :33922-33928
[2]   HOXB4-induced expansion of adult hematopoietic stem cells ex vivo [J].
Antonchuk, J ;
Sauvageau, G ;
Humphries, RK .
CELL, 2002, 109 (01) :39-45
[3]   Nf1 and Gmcsf interact in myeloid leukemogenesis [J].
Birnbaum, RA ;
O'Marcaigh, A ;
Wardak, Z ;
Zhang, YY ;
Dranoff, G ;
Jacks, T ;
Clapp, DW ;
Shannon, KM .
MOLECULAR CELL, 2000, 5 (01) :189-195
[4]   Effects of overexpression of the SH2-containing inositol phosphatase SHIP on proliferation and apoptosis of erythroid AS-E2 cells [J].
Boer, AK ;
Drayer, AL ;
Vellenga, E .
LEUKEMIA, 2001, 15 (11) :1750-1757
[5]  
Bradford GB, 1997, EXP HEMATOL, V25, P445
[6]   Differential regulation of B cell development, activation, and death by the Src homology 2 domain-containing 5′ inositol phosphatase (SHIP) [J].
Brauweiler, A ;
Tamir, I ;
Dal Porto, J ;
Benschop, RJ ;
Helgason, CD ;
Humphries, RK ;
Freed, JH ;
Cambier, JC .
JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 191 (09) :1545-1554
[7]   SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization [J].
Carver, DJ ;
Aman, MJ ;
Ravichandran, KS .
BLOOD, 2000, 96 (04) :1449-1456
[8]  
Chacko GW, 1996, J IMMUNOL, V157, P2234
[9]   Serum cytokine level fluctuations in chemotherapy-induced myelosuppression [J].
Chen, YM ;
WhangPeng, J ;
Liu, JM ;
Kuo, BIT ;
Wang, SY ;
Tsai, CM ;
Perng, RP .
JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 1996, 26 (01) :18-23
[10]   Hematopoietic stem cell quiescence maintained by p21cip1/waf1 [J].
Cheng, T ;
Rodrigues, N ;
Shen, HM ;
Yang, YG ;
Dombkowski, D ;
Sykes, M ;
Scadden, DT .
SCIENCE, 2000, 287 (5459) :1804-1808