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

• Published in: Molecular and cellular biology 2003-12, Vol.23 (24), p.9349-9360
• Main Authors: Scott, L M, Priestley, G V, Papayannopoulou, T
• Format: Article
• Language: English
• Subjects: phenylhydrazine
• ISSN: 0270-7306
• DOI: 10.1128/MCB.23.24.9349-9360.2003

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 super(-/-) 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 beta 1 integrin-conditional knockouts.