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(p27kip1) 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 p27kip1 could reverse the senescent features of BM‐MSCs via down‐regulating p27kip1 expression. When purified CD4+ T cells were incubated with PTEN or p27kip1‐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 p27kip1 expression. J. Cell. Biochem. 116: 1583–1594, 2015. © 2015 Wiley Periodicals, Inc.