Bone marrow dysfunction in mice lacking the cytokine receptor gp130 in endothelial cells

Abstract

In vitro studies suggest that bone marrow endothelial cells contribute to multilineage hematopoiesis, but this function has not been studied in vivo. We used a Cre/loxP-mediated recombination to produce mice that lacked the cytokine receptor subunit gp130 in hematopoietic and endothelial cells. Although normal at birth, the mice developed bone marrow dysfunction that was accompanied by splenomegaly caused by extramedullary hema- IntroductionThe interleukin-6 (IL-6) family of cytokines includes IL-6, IL-11, oncostatin M, leukemia inhibitory factor, ciliary neurotrophic factor, and cardiotropin-1. All these cytokines bind to receptors that share the signaling subunit gp130. 1,2 Because many cells express these receptors, gp130-dependent signaling is thought to have numerous important functions. Indeed, mice lacking gp130 in all cells die of diverse morphologic abnormalities during development, 3 and postnatally induced deletion of gp130 in all cells causes defects in many systems. 4 Because gp130 is so widely expressed, clarifying gp130-dependent functions requires targeted deletion of gp130 in specific cell types. For example, myocyte-restricted deletion of gp130 in mice causes apoptosis that results in heart failure. 5 Global deletion of gp130 decreases hematopoietic progenitors in fetal liver, 3 and postnatally induced deletion of gp130 causes hematopoietic defects. 4 It is unknown whether these abnormalities result from loss of gp130 signaling in hematopoietic cells, other cells in the microenvironment, or both. Cultured hematopoietic cells respond directly to IL-6-related cytokines. [6][7][8][9][10] However, endothelial cells also express gp130, 11 and there is a close developmental relationship between hematopoietic and endothelial cells that may arise from hemangioblasts or specialized hemogenic endothelial cells in early fetal life. [12][13][14][15][16] Cultured endothelial cells derived from adult bone marrow or fetal yolk sac support multilineage hematopoiesis, 12,13,17,18 but this broad function has not been demonstrated in vivo. Stimulation of megakaryocyte progenitors with some chemokines, but not with IL-6 or IL-11, causes them to adhere to bone marrow endothelial cells, which enhances thrombopoiesis in thrombopoietin-deficient mice. 19 This study provides evidence that endothelial cells contribute to hematopoiesis in one lineage, but it does not address whether IL-6 family cytokines participate in cross-talk between hematopoietic and endothelial cells during hematopoiesis.Here, we used the Cre/loxP-mediated gene recombination to selectively delete gp130 in hematopoietic and endothelial cells of mice. Although hematopoiesis was normal throughout the fetal and neonatal periods, bone marrow dysfunction developed in adult mice. Intrinsic defects in hematopoietic stem and progenitor cells were not apparent even when anemia was severe. Transplantation experiments revealed that hematopoiesis required the expression of gp130 in the bone marrow microenvironment. These data provide evidence that gp130-depend...

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