PTEN/Akt-p27(kip1) Signaling Promote the BM-MSCs Senescence and Apoptosis in SLE Patients.

Abstract

Recent studies showed that allogeneic bone marrow (BM)-mesenchymal stem cells transplantation (MSCT) was effective in systemic lupus erythematosus (SLE) patients and lupus-prone mice. However, syngeneic BM-MSCT was ineffective. Previous studies, including ours, revealed that BM-MSCs from SLE patients exhibited early signs of senescence and apoptosis such as slow proliferation, increasing senescence-associated β-galactosidase (SA-β-gal)-positive cells and Annexin V-positive cells, and caspase cascade activation. The abnormalities of BM-MSCs might be associated with the pathogenesis of SLE. In this study, we aimed to determine the molecular mechanism of senescent BM-MSCs from SLE patients. We found that the expression of protein 27 kinase inhibition protein 1(p27(kip1) ) increased significantly, which was regulated by phosphatase and tensin homology deleted on chromosome 10 (PTEN)/protein kinase B (Akt) signaling in SLE BM-MSCs. Knockdown of PTEN or p27(kip1) could reverse the senescent features of BM-MSCs via down-regulating p27(kip1) expression. When purified CD4(+) T cells were incubated with PTEN or p27(kip1) -silenced SLE BM-MSCs, the ratio of regulatory T (Treg)/T helper type 17 (Th17) cells increased significantly by enhancing regulatory cytokines (IL-10 and TGF-β) and reducing pro-inflammatory cytokines (IL-17 and IL-6). Taken together, we demonstrated that PTEN/Akt signaling played an essential role in the senescent and apoptotic BM-MSCs from SLE patients by up-regulating p27(kip1) expression.

• Authors: Wei Tan, Zhifeng Gu, Biyu Shen, Jinxia Jiang, Yan Meng, Zhanyun Da, Hong Liu, Tao Tao, Chun Cheng
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 116 Issue 8 Pg. 1583-94 (Aug 2015) ISSN: 1097-4644 [Electronic] United States
• PMID: 25649549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• CDKN1B protein, human
• Cyclin-Dependent Kinase Inhibitor p27
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adolescent
• Adult
• Apoptosis
• Cell Proliferation
• Cells, Cultured
• Cellular Senescence
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Gene Expression Regulation
• Humans
• Lupus Erythematosus, Systemic (metabolism, pathology)
• Mesenchymal Stem Cells (metabolism, pathology)
• PTEN Phosphohydrolase (metabolism)
• Signal Transduction
• Young Adult