title: The influence of immunosuppressive drugs on neural stem/progenitor cell fate in vitro.
abstract: In allogenic and xenogenic transplantation, adequate immunosuppression plays a major role in graft survival, especially over the long term. The effect of immunosuppressive drugs on neural stem/progenitor cell fate has not been sufficiently explored. The focus of this study is to systematically investigate the effects of the following four different immunotherapeutic strategies on human neural progenitor cell survival/death, proliferation, metabolic activity, differentiation and migration in vitro: (1) cyclosporine A (CsA), a calcineurin inhibitor; (2) everolimus (RAD001), an mTOR-inhibitor; (3) mycophenolic acid (MPA, mycophenolate), an inhibitor of inosine monophosphate dehydrogenase and (4) prednisolone, a steroid. At the minimum effective concentration (MEC), we found a prominent decrease in hNPCs' proliferative capacity (BrdU incorporation), especially for CsA and MPA, and an alteration of the NAD(P)H-dependent metabolic activity. Cell death rate, neurogenesis, gliogenesis and cell migration remained mostly unaffected under these conditions for all four immunosuppressants, except for apoptotic cell death, which was significantly increased by MPA treatment.
authors.affiliation: Department of Neurosurgery, University Hospital, Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany. Electronic address: Marco.Skardelly@med.uni-tuebingen.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Skardelly
authors.forename: Anja
authors.initials: A
authors.lastname: Glien
authors.forename: Claudia
authors.initials: C
authors.lastname: Groba
authors.forename: Nadine
authors.initials: N
authors.lastname: Schlichting
authors.forename: Manja
authors.initials: M
authors.lastname: Kamprad
authors.forename: Juergen
authors.initials: J
authors.lastname: Meixensberger
authors.forename: Javorina
authors.initials: J
authors.lastname: Milosevic
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005455:Fluorescent Antibody Technique; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000494:pharmacology; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D011239:Prednisolone / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D011239:Prednisolone; D009173:Mycophenolic Acid; D020123:Sirolimus
keywords: 1-methyl-4-phenylpyridinium; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; 4',6-diamidino-2-phenylindole; 5-bromo-2-deoxyuridine; ANOVA; BBB; BSA; BrdU; CNS; CsA; Cyclosporine A; DAPI; EGF; ELISA; Everolimus; FBS; FGF-2; GFAP; Human; IMPDH; Immunosuppressive drugs; MEC; MHC; MPA; MPP(+); MTT; Mycophenolate; NADP; Neural progenitor cells; PBS; PI; Phosphate buffered saline; Prednisolone; TUJ1; Transplantation; analysis of variance; blood-brain barrier; bovine serum albumin; central nervous system; cyclosporine A; enzyme-linked immunosorbent assay; epidermal growth factor; fetal bovine serum; fibroblast growth factor 2; glial fibrillary acidic protein; hNPCs; human neural progenitor cells; inosine 5-monophosphate dehydrogenase; major histocompatibility complex; minimum effective concentration; mycophenolate; neuronal class III β-tubulin; nicotinamide adenine dinucleotide phosphate; propidium iodide