title: Deletion of alpha4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing.
abstract: We have explored the functional implications of inducible alpha4 integrin deletion during adult hematopoiesis by generating a conditional-knockout mouse model, and we show that alpha4 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 alpha4 integrin. Moreover, in transplantation studies, homing of alpha4(-/-) 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 alpha4 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 alpha4 integrin-null chimeras and beta1 integrin-conditional knockouts.
authors.affiliation: Division of Hematology, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195-7710, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Priestley
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
mesh_terms: D000743:Anemia, Hemolytic / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002465:Cell Movement; D003114:Colony-Forming Units Assay; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis; D039441:Integrin alpha4 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012038:Regeneration; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology
chemical_list: D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D005472:Fluorouracil