Transforming growth factor- 1 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 factor1 (TGF1) a possible candidate, since TGF1 has effects on CD34 cells and is produced by stromal cells, which provide niches for maintenance and proliferation of stem/ progenitor cells. TGF1 significantly restored SDF-1–induced chemotaxis and sustained adhesion responses in cord blood CD34 cells preexposed to SDF-1. Effects of TGF1 were dependent on the dose and duration of TGF1 pretreatment. Phosphorylation of extracellular signal-regulated kinase 1 (Erk1)/Erk2 was implicated in TGF1 modulation of migratory and adhesion responses to SDF-1. Our results indicate that low levels of TGF1 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. (Blood. 2005;106:485-493)