The gp130 Cytokine IL-11 Regulates Engraftment of Vav1-/- Hematopoietic Stem and Progenitor Cells in Lethally Irradiated Recipients

Abstract

During bone marrow transplantation (BMT), hematopoietic stem and progenitor cells (HSPCs) respond to signals from the hematopoietic microenvironment (HM) by coordinately activating molecular pathways through Rho GTPases, including Rac. We have previously shown that deletion of Vav1, a hematopoietic-specific activator of Rac, compromises engraftment of transplanted adult HSPCs without affecting steady-state hematopoiesis in adult animals. Here, we show that Vav1^-/- fetal HSPCs can appropriately seed hematopoietic tissues during ontogeny but cannot engraft into lethally irradiated recipients. We demonstrate that the engraftment defect of Vav1^-/- HSPCs is abrogated in the absence of irradiation and demonstrate that Vav1 is critical for the response of HSPCs to the proinflammatory cytokine interleukin-11 (IL-11) that is upregulated in the marrow of irradiated recipients. Vav1^-/- HSPCs display abnormal proliferative responses to IL-11 in vitro and dysregulated activation of pathways critical to engraftment of HSPCs. The engraftment of Vav1^-/- HSPCs can be partially rescued in irradiated recipients treated with an anti-IL-11 antibody. These data suggest that HSPCs may respond to different functional demands by selective usage of the IL-11-Vav-Rac pathway, contextualizing further the recent view that HSPCs capable of reconstituting the blood system following transplantation might be distinct from those supporting hematopoiesis during homeostatic conditions. This article is protected by copyright. All rights reserved.

Irradiation used as a conditioning regimen for BMT causes profound changes in the hematopoietic microenvironment (HM), including the release of soluble factors. Among these factors, IL-11 increases after irradiation and regulates proliferation of HSPCs. Vav1-/- HSPCs are unable to integrate signals from IL-11 and SDF1α, and therefore display a very limited reconstitution potential in lethally irradiated recipients

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