title: Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients.
abstract: Previous studies have indicated that bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired proliferation, differentiation, and immune modulation capacities. Thus, MSCs may be associated with the pathogenesis of SLE. The aim of this study was to determine whether MSCs from SLE patients were senescent and to determine the mechanism underlying this phenomenon. MSCs from both untreated and treated SLE patients showed characteristics of senescence. The expression of p16(INK4A) was significantly increased, whereas levels of CDK4, CDK6 and p-Rb expression were decreased in the MSCs from both untreated and treated SLE patients. Knockdown of p16(INK4A) expression reversed the senescent features of MSCs and upregulated TGF-β expression. In vitro, when purified CD4+ T cells were incubated with p16(INK4A)-silenced SLE MSCs, the percentage of regulatory T cells was significantly increased. Further, we have found that p16(INK4A) promotes MSC senescence via the suppression of the extracellular signal regulated kinase (ERK) pathway. p16(INK4A) knockdown up-regulated ERK1/2 activation. Our results demonstrated that MSCs from SLE patients were senescent and that p16 (INK4A) plays an essential role in the process by inhibiting ERK1/2 activation.
authors: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China. guzhifeng@126.com
authors: Zhifeng
authors: Z
authors: Gu
authors: Xiaolei
authors: X
authors: Cao
authors: Jinxia
authors: J
authors: Jiang
authors: Liren
authors: L
authors: Li
authors: Zhanyun
authors: Z
authors: Da
authors: Hong
authors: H
authors: Liu
authors: Chun
authors: C
authors: Cheng
mesh_terms: D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3