title: Preconditioning of stem cells by oxytocin to improve their therapeutic potential.
abstract: Principal limitation of cell therapy is cell loss after transplantation because of the interplay between ischemia, inflammation, and apoptosis. We investigated the mechanism of preconditioning of mesenchymal stem cells (MSCs) with oxytocin (OT), which has been proposed as a novel strategy for enhancing therapeutic potential of these cells in ischemic heart. In this study, we demonstrate that rat MSCs express binding sites for OT receptor and OT receptor transcript and protein as detected by RT-PCR and immunofluorescence, respectively. In response to OT (10(-10) to 10(-6) M) treatment, MSCs respond with rapid calcium mobilization and up-regulation of the protective protein kinase B (PKB or Akt) and phospho-ERK1/2 proteins. In OT-stimulated cells, phospho-Akt accumulates intracellularly close to the mitochondrial marker cytochrome c oxidase subunit 4. Functional analyses reveal the involvement of Akt/ERK1/2 pathways in cell proliferation, migration, and protection against the cytotoxic and apoptotic effects of hypoxia and serum deprivation. In addition, OT preconditioning increases MSC glucose uptake. Genes with angiogenic, antiapoptotic, and cardiac antiremodeling properties, such as heat shock proteins (hsps) HSP27, HSP32, HSP70, vascular endothelial growth factor, thrombospondin, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, and matrix metalloproteinase-2, were also up-regulated upon OT exposure. Moreover, coculture with OT-preconditioned MSC reduces apoptosis, as measured using terminal transferase dUTP nick end labeling assay in newborn rat cardiomyocytes exposed to hypoxia and reoxygenation. In conclusion, these results indicate that OT treatment evokes MSC protection through both intrinsic pathways and secretion of cytoprotective factors. Ex vivo cellular treatment with OT represents an attractive strategy aimed to maximize the biological and functional properties of effector cells.
authors.affiliation: Centre de Recherche, Department of Medicine, Université de Montréal, Québec, Canada. noiseuxn@videotron.ca
authors.forename: Nicolas
authors.initials: N
authors.lastname: Noiseux
authors.forename: Mélanie
authors.initials: M
authors.lastname: Borie
authors.forename: Alexandra
authors.initials: A
authors.lastname: Desnoyers
authors.forename: Ahmed
authors.initials: A
authors.lastname: Menaouar
authors.forename: Louis Mathieu
authors.initials: LM
authors.lastname: Stevens
authors.forename: Samer
authors.initials: S
authors.lastname: Mansour
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Danalache
authors.forename: Denis-Claude
authors.initials: DC
authors.lastname: Roy
authors.forename: Marek
authors.initials: M
authors.lastname: Jankowski
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gutkowska
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010121:Oxytocin / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018045:Receptors, Oxytocin; D010121:Oxytocin; D003576:Electron Transport Complex IV; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium