title: Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway.
abstract: We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated β-galactosidase (SA-β-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1x106 of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.|Department of Emergency Medicine, The Yangzhou First People's Hospital, Yangzhou, Jiangsu Province 225001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Guijian
authors.initials: G
authors.lastname: Feng
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Da
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Genkai
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Xinhang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.|Department of Rheumatology, Affiliated First Hospital of Xiamen University, Xiamen, Fujian Province 361000, China.
authors.forename: Guixiu
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.|Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu Province 226001, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
mesh_terms: D000818:Animals; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008181:Lupus Nephritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D001616:beta-Galactosidase; D020123:Sirolimus
keywords: immunoregulation; mesenchymal stem cells (MSCs); rapamycin (RAPA); senescence; systemic lupus erythematosus (SLE)