Antiproliferative Effects of Local Anesthetics on Mesenchymal Stem Cells Potential Implications for Tumor Spreading and Wound Healing

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/propidiurn iodide staining (early apoptotic cells/necrotic cells). Measurements of mitochondria] function in intact and permeabilized cells, transcriptional changes, and changes in nuclear factor K-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 mu M consistent with cell cycle delay or arrest at the G(0/1)-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.