Deletion of α4 Integrins from Adult Hematopoietic Cells Reveals Roles in Homeostasis, Regeneration, and Homing

Abstract

We have explored the functional implications of inducible α4 integrin deletion during adult hematopoiesis by generating a conditional-knockout mouse model, and we show that α4 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 α4 integrin. Moreover, in transplantation studies, homing of α4 ^−/− 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 α4 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 α4 integrin-null chimeras and β1 integrin-conditional knockouts.

ACKNOWLEDGMENTS

We acknowledge the technical assistance of Denise Farrar, Betty Nakamoto, Alex Rohde, and Vivian Zafiropoulos. We are grateful to Ken Peterson for his contribution in the early stages of this work. James Downing (St. Jude's Children's Research Hospital, Memphis, Tenn.) kindly provided the MSCV-cre-iresGFP plasmid.

This work was supported by National Institutes of Health grant numbers HL46557 and HL58734, which were awarded to T.P.