Transforming growth factor-β1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12

Disruption of stromal cell-derived factor-1 (SDF-1/CXCL12 [CXC chemokine ligand 12]) interaction leads to mobilization of stem/ progenitor cells from bone marrow to circulation. However, prolonged exposure of CD34(+) cells to SDF-1 desensitizes them to SDF-1. So how do cells remain responsive to SDF-1 in vivo when they are continuously exposed to SDF-1 ? We hypothesized that one or more mechanisms mediated by cytokines exist that could modulate SDF-1 responsiveness of CD34(+) cells and the desensitization process. We considered transforming growth factor-beta 1 (TGF-beta 1) a possible candidate, since TGF-beta 1 has effects on CD34(+) cells and is produced by stromal cells, which provide niches for maintenance and proliferation of stem/ progenitor cells. TGF-beta 1 significantly restored SDF-1-induced chemotaxis and sustained adhesion responses in cord blood CD34(+) cells preexposed to SDF-1. Effects of TGF-beta 1 were dependent on the dose and duration of TGF-beta 1 pretreatment. Phosphorylation of extracellular signal-regulated kinase 1 (Erk1)/Erk2 was implicated in TGF-beta 1 modulation of migratory and adhesion responses to SDF-1. Our results indicate that low levels of TGF-beta 1 can modulate SDF-1 responsiveness of CD34(+) cells and thus may facilitate SDF-1-mediated retention and nurturing of stem/progenitor cells in bone marrow.