Tatiana Ulyanova

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

To delineate the role of specific members of β₁ integrins in stress erythropoiesis in the adult, we compared the response to phenylhydrazine stress in 3 genetically deficient models. The survival of β₁-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 β₁(Δ/Δ) 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 β₁-deficient mice, α₄(Δ/Δ) mice showed only a kinetic delay in recovery and similar to β₁(Δ/Δ), terminal maturation defects in both bone marrow and spleen, which were not present in VCAM-1(Δ/Δ) mice. Convergence of information from these comparative studies lends new insight to the distinct in vivo roles of α₄ and α₅ integrins in erythroid stress, suggesting that the presence of mainly α₅β₁ 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 α₄ or of both α₅ and α₄, is important for completion of terminal maturation steps.

The macrophage contribution to stress erythropoiesis: when less is enough

Although the importance of native bone marrow and spleen macrophages in enhancing baseline and stress erythropoiesis has been emphasized over several decades, their kinetic and phenotypic changes during a variety of stress responses have been unclear. Furthermore, whether monocyte-derived recruited macrophages can functionally substitute for inadequate or functionally impaired native macrophages has been controversial and seem to be not only tissue- but also stress-type dependent. To provide further insight into these issues, we made detailed observations at baseline and post-erythroid stress (E-stress) in 2 mouse models with genetically depressed macrophage numbers and compared them to their controls. We documented that, irrespective of the stress-induced (hemolytic or post-erythropoietin [Epo]) treatment, only native CD11b(lo) splenic macrophages expand dramatically post-stress in normal mice without significant changes in the monocyte-derived CD11b(hi) subset. The latter remained a minority and did not change post-stress in 2 genetic models lacking either Spi-C or VCAM-1 with impaired native macrophage proliferative expansion. Although CD11b(lo) macrophages in these mice were one-fifth of normal at their peak response, surprisingly, their erythroid response was not compromised and was similar to controls. Thus, despite the prior emphasis on numerical macrophage reliance to provide functional rescue from E-stress, our data highlight the importance of previously described non-macrophage-dependent pathways activated under certain stress conditions to compensate for low macrophage numbers.

Is the post-transplantation treatment with AMD beneficial?

Recent data have suggested novel ways to enhance donor cell engraftment by treating transplanted recipients with CXCR4/CXCL12 inhibitors, thereby expanding the biologic potential of these molecules primarily used for mobilization purposes. We tested whether repeated pulse inhibitions of CXCR4/CXCL12 signaling using AMD, an inhibitor of CXCR4/CXCL12 signaling, would enhance engraftment in non-myeloablated murine recipients, similar to data published in a myeloablative setting. We documented an increased proportion of circulating neutrophils (both donor- and host-derived) in the AMD-treated group, but this increase was not kinetically influenced by AMD treatment and multilineage engraftment was not enhanced. Although our results with neutrophils are similar to recent clinical data in neutropenic patients chronically treated with AMD, the absence of multilineage engraftment diverges from data in myeloablated recipients. We conclude that pulses of mobilization by AMD post transplantation do not enhance multilineage engraftment.