title: APRIL and BAFF proteins increase proliferation of human adipose-derived stem cells through activation of Erk1/2 MAP kinase.
abstract: Human adipose-derived stem cells (hASC) are mesenchymal stem cells with reduced immunogenicity and the ability to modulate immune responses. APRIL and BAFF proteins are overexpressed in inflammatory and autoimmune diseases for which allogeneic hASC therapy is currently under clinical investigation. Modification of hASC properties by the tissue microenvironment could be a critical factor in patient outcome and is still not well understood. Our aim was to characterize the APRIL/BAFF system in hASC by analyzing the ligand and receptor expression patterns, the effects mediated by APRIL and BAFF on hASC, and the underlying signaling. We found that hASC express the tumor necrosis factor proteins APRIL (a proliferation-inducing ligand) and BAFF (B cell-activator factor) as well as their receptors TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), BCMA (B cell maturation antigen) and the BAFF-specific receptor (BAFF-R). APRIL and BAFF secretion was differentially enhanced by CXCL12 and interferon (IFN)-γ, implicated in hASC-mediated migration and immunosuppression, respectively. In addition, APRIL and BAFF induced rapid phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt kinases and promoted an increase in hASC proliferation, without affecting the immunosuppressive capacity of these cells. The use of specific chemical inhibitors indicated that the PI3K transduction pathway is involved in hASC basal growth and that APRIL- and BAFF-mediated effects are ERK-dependent. These results provide new information about the molecular mechanisms that underlie APRIL and BAFF secretion and signaling in hASC, and are of special relevance for the use of allogeneic hASC as therapeutic tools.
authors: Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, 28049 Madrid, Spain.
authors: Manuela
authors: M
authors: Zonca
authors: Pablo
authors: P
authors: Mancheño-Corvo
authors: Olga
authors: O
authors: DelaRosa
authors: Santos
authors: S
authors: Mañes
authors: Dirk
authors: D
authors: Büscher
authors: Eleuterio
authors: E
authors: Lombardo
authors: Lourdes
authors: L
authors: Planelles
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000328:Adult; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D015850:Interleukin-6; D016209:Interleukin-8; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3