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Molecular and Cellular Biology, December 2003, p. 9349-9360, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9349-9360.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Deletion of {alpha}4 Integrins from Adult Hematopoietic Cells Reveals Roles in Homeostasis, Regeneration, and Homing

Linda M. Scott,{dagger} Gregory V. Priestley, and Thalia Papayannopoulou*

Division of Hematology, University of Washington, Seattle, Washington 98195-7710

Received 24 June 2003/ Returned for modification 15 August 2003/ Accepted 18 September 2003

We have explored the functional implications of inducible {alpha}4 integrin deletion during adult hematopoiesis by generating a conditional-knockout mouse model, and we show that {alpha}4 integrin-deficient hematopoietic progenitor cells accumulate in the peripheral blood soon after interferon-induced gene deletion. Although their numbers gradually stabilize at a lower level, progenitor cell influx into the circulation continues at above-normal levels for more than 50 weeks. Concomitantly, a progressive accumulation of progenitors occurs within the spleen. In addition, the regeneration of erythroid and myeloid progenitor cells is delayed during stress hematopoiesis induced by phenylhydrazine or by 5-fluorouracil, suggesting impairment in early progenitor expansion in the absence of {alpha}4 integrin. Moreover, in transplantation studies, homing of {alpha}4-/- cells to the bone marrow, but not to the spleen, is selectively impaired, and short-term engraftment is critically delayed in the early weeks after transplantation. Thus, conditional deletion of {alpha}4 integrin in adult mice is accompanied by a novel hematopoietic phenotype during both homeostasis and recovery from stress, a phenotype that is distinct from the ones previously described in {alpha}4 integrin-null chimeras and ß1 integrin-conditional knockouts.

* Corresponding author. Mailing address: Division of Hematology, University of Washington, Box 357710, 1705 NE Pacific St., Seattle, WA 98195-7710. Phone: (206) 543-5756. Fax: (206) 543-3050. E-mail: thalp{at}u.washington.edu.

{dagger} Present address: University Department of Hæmatology, Cambridge Institute of Medical Research, Cambridge CB2 2XY, United Kingdom.

Molecular and Cellular Biology, December 2003, p. 9349-9360, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9349-9360.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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