Upregulation of p16^INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients

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• 作者：Zhifeng Gu ; Xiaolei Cao ; Jinxia Jiang ; Liren Li ; Zhanyun Da ; Hong Liu ; Chun Cheng
• 关键词：Mesenchymal stem cells ; Systemic lupus erythematosus ; Senescence ; p16INK4A ; Immune regulation
• 刊名：Cellular Signalling
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：24
• 期：12
• 页码：2307-2314
• 全文大小：990 K

文摘

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-¦Â 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.