title: Transforming growth factor-{beta}1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12.
abstract: 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-beta1 (TGF-beta1) a possible candidate, since TGF-beta1 has effects on CD34+ cells and is produced by stromal cells, which provide niches for maintenance and proliferation of stem/progenitor cells. TGF-beta1 significantly restored SDF-1-induced chemotaxis and sustained adhesion responses in cord blood CD34+ cells preexposed to SDF-1. Effects of TGF-beta1 were dependent on the dose and duration of TGF-beta1 pretreatment. Phosphorylation of extracellular signal-regulated kinase 1 (Erk1)/Erk2 was implicated in TGF-beta1 modulation of migratory and adhesion responses to SDF-1. Our results indicate that low levels of TGF-beta1 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.
authors.affiliation: Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Research Institute No. 2 Bldg, Rm 302, 950 W Walnut St, Indianapolis, IN 46202-5181, USA. sunbasu@iupui.edu
authors.forename: Sunanda
authors.initials: S
authors.lastname: Basu
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D000199:Actins / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005312:Fetal Blood / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002118:Calcium