title: Adipogenic differentiation is impaired in replicative senescent human subcutaneous adipose-derived stromal/progenitor cells.
abstract: We demonstrate that adipose-derived stromal/progenitor cells isolated from abdominal subcutaneous fat pads of adult donors successively enter replicative senescence after long-term cultivation. This is characterized by enlarged cell size, flattened morphology, and upregulated senescence-associated β-galactosidase activity. Moreover, the senescence- associated cyclin-dependent kinase inhibitors p16(Ink4A) and p21(Cip1) were induced correlating with activation of the G1/S cell cycle inhibitor retinoblastoma protein and terminal proliferation arrest. The number of cells in the adipose-derived stromal/progenitor cell population with high adipogenic capacity declined inversely with the increase of senescent cells. Adipogenic hormone cocktail induced expression of the adipogenic key regulators peroxisome proliferator-activated receptor-γ2 and CCAAT/enhancer-binding protein α was significantly reduced in senescent adipose-derived stromal/ progenitor cells. Furthermore, the expression of the adipogenic differentiation genes fatty acid binding protein-4, adiponectin, and leptin and the formation of fat droplets were impaired. We conclude cellular senescence contributes to dysfunctions in adipose-derived stromal/progenitor cell replication, adipogenesis, triglyceride storage, and adipokine secretion.
authors: *These authors contributed equally to this work.
authors: Maria C
authors: MC
authors: Mitterberger
authors: Stefan
authors: S
authors: Lechner
authors: Monika
authors: M
authors: Mattesich
authors: Werner
authors: W
authors: Zwerschke
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D023081:CCAAT-Binding Factor / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008875:Middle Aged; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D023081:CCAAT-Binding Factor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D012313:RNA
keywords: Adipogenesis; Adipokine; Adipose-derived stromal/progenitor cells; Aging; C/EBPα; PPARγ2; Proliferation; Retinoblastoma protein.; Senescence; p16Ink4A; p21Cip1; p53