title: Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing.
abstract: BACKGROUND
  Mesenchymal stem cells (MSC) are self-renewing clonal progenitor cells of nonhematopoietic tissues that exhibit a marked tropism to wounds and tumors. The authors' studies aimed at exploring how local anesthetics would affect MSC biology.
  
  
  METHODS
  Proliferation, colony formation, in vitro wound healing, and bone differentiation assays of culture-expanded bone-marrow-derived murine MSC were performed in the presence of increasing concentrations of lidocaine, ropivacaine, and bupivacaine. Cytotoxicity was monitored by measuring lactate dehydrogenase activity and phosphatidylserine exposure/propidium iodide staining (early apoptotic cells/necrotic cells). Measurements of mitochondrial function in intact and permeabilized cells, transcriptional changes, and changes in nuclear factor κ-light-chain-enhancer of activated B cells signaling in MSC treated with ropivacaine were used to further characterize the biologic effects of local anesthetics on MSC.
  
  
  RESULTS
  All local anesthetics reduced MSC proliferation at 100 μM, consistent with cell cycle delay or arrest at the G0/1-S phase transition. They increased lactate dehydrogenase release and the number of annexin V-positive MSC but not necrotic MSC. Colony formation was decreased, differentiation into osteoblasts impaired, and in vitro wound healing delayed. Mitochondrial respiration and adenosine 5'-triphosphate concentrations were reduced. Microarray analysis revealed significant expression changes in lysosomal genes and genes controlling sterol metabolism, indicating an impaired phospholipid metabolism in the lysosome. Multiple transcriptional programs related to cell differentiation, tumorigenesis, and metastasis were negatively affected by ropivacaine.
  
  
  CONCLUSIONS
  The authors' studies demonstrate that local anesthetics significantly affect important aspects of MSC biology. These experiments provide novel rationales for the perioperative use of local anesthetics in patients with cancer but also highlight the potentially detrimental effects of local anesthetics on wound healing.
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Awad
authors.forename: Mamoona
authors.initials: M
authors.lastname: Rahman
authors.forename: Jianhua
authors.initials: J
authors.lastname: Feng
authors.forename: Phing-How
authors.initials: PH
authors.lastname: Lou
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Lavinia
authors.initials: L
authors.lastname: Ionescu
authors.forename: Hélène
authors.initials: H
authors.lastname: Lemieux
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D000779:Anesthetics, Local