Enhancement of intracellular signaling associated with hematopoietic progenitor cell survival in response to SDF-1/CXCL12 in synergy with other cytokines

Abstract

Stromal cell–derived factor 1 (SDF-1/CXCL12) is a multifunctional cytokine. We previously reported that myelopoiesis was enhanced in SDF-1α transgenic mice, probably due in part to SDF-1α enhancement of myeloid progenitor cell (MPC) survival. To understand signaling pathways involved in this activity, we studied the effects on factor-dependent cell line MO7e cells incubated with SDF-1α alone or in combination with other cytokines. SDF-1α induced transient activation of extracellular stress–regulated kinase (ERK1/2), ribosomal S6 kinase (p90RSK) and Akt, molecules implicated in cell survival. Moreover, ERK1/2, p90RSK, and Akt were synergistically activated by SDF-1α in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), Steel factor (SLF), or thrombopoietin (TPO). Similar effects were seen after pretreatment of MO7e cells with SDF-1α followed by stimulation with the other cytokines, suggesting a priming effect of SDF-1α. Nuclear factor-κB (NF-κB) did not appear to be involved in SDF-1α actions, alone or in combination with other cytokines. These intracellular effects were consistent with enhanced myeloid progenitor cell survival by SDF-1α after delayed addition of growth factors. SDF-1α alone supported survival of highly purified human cord blood CD34+++ cells, less purified human cord blood, and MO7e cells; this effect was synergistically enhanced when SDF-1α was combined with low amounts of other survival-promoting cytokines (GM-CSF, SLF, TPO, and FL). SDF-1 may contribute to maintenance of MPCs in bone marrow by enhancing cell survival alone and in combination with other cytokines.