Combinatorial and distinct roles of α5 and α4 integrins in stress erythropoiesis in mice

To delineate the role of specific members of beta(1) integrins in stress erythropoiesis in the adult, we compared the response to phenylhydrazine stress in 3 genetically deficient models. The survival of beta 1-conditionally deficient mice after phenylhydrazine is severely compromised because of their inability to mount a successful life saving splenic erythroid response, a phenotype reproduced in beta(Delta/Delta)(1) reconstituted animals. The response of bone marrow to phenylhydrazine-induced stress was, unlike that of spleen, appropriate in terms of progenitor cell expansion and mobilization to peripheral blood although late differentiation defects qualitatively similar to those in spleen were present in bone marrow. In contrast to beta(1)-deficient mice, alpha 4(Delta/Delta) mice showed only a kinetic delay in recovery and similar to beta(Delta/Delta)(1), terminal maturation defects in both bone marrow and spleen, which were not present in VCAM-1(Delta/Delta) mice. Convergence of information from these comparative studies lends new insight to the distinct in vivo roles of alpha(4) and alpha(5) integrins in erythroid stress, suggesting that the presence of mainly alpha(5)beta(1) integrin in all hematopoietic progenitor cells interacting with splenic microenvironmental ligands/cells is instrumental for their survival and accumulation during hemolytic stress, whereas presence of alpha(4), or of both alpha(5) and alpha 4, is important for completion of terminal maturation steps. (Blood. 2011; 117(3): 975-985)