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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2002-12-3939.
Submitted December 30, 2002
Accepted June 23, 2003
Homeostasis and regeneration of the hematopoietic stem cell pool is altered in SHIP-deficient mice
Cheryl D Helgason*, Jennifer Antonchuk, Caroline Bodner, and R Keith Humphries
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
* Corresponding author; email: chelgaso{at}bccancer.bc.ca.
SHIP is an important negative regulator of cytokine and immune receptor signalling. 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 wildtype 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 CRU 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 transplanted with SHIP-deficient cells compared to 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.
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