title: Lactate modulates gene expression in human mesenchymal stem cells.
abstract: OBJECTIVE
  Surgical wounds are characterised by elevated tissue lactate concentrations. This accumulated lactate is capable of stimulating collagen synthesis and new vessel growth as well. Recently, it has been shown in vivo that lactate is also able to favour homing of stem cells. The aim of this investigation was to test the hypothesis that lactate has an impact on gene expression of mesenchymal stem cells (MSC).
  
  
  METHODS
  MSC were isolated from human bone marrow using the density gradient technique and incubated with alpha-methoxyethoxymethyl containing 10% fetal calf serum at 37 degrees C under 95% air and 5% CO(2). Cultured MSC were characterised by in vitro differentiation assays and fluorescence-activated cell sorting (FACS) analysis. Characterised MSC were treated with 15 mM lactate for different time periods (1, 6 and 24 h and 3 and 7 days). Gene expression analysis was performed using a custom-designed oligonucleotide microarray. A significant alteration of gene expression was defined as a two-fold stimulation or inhibition. The phenotype of MSC was investigated by FACS analysis of specific surface epitope patterns.
  
  
  RESULTS
  Gene expression analysis shows 63 up- and 51 down-regulated genes after 1 h of treatment, 45 up- and 47 down-regulated genes after 6 h of treatment, 57 up- and 72 down-regulated genes after 24 h of treatment, 103 up- and 28 down-regulated genes after 3 days of treatment and 50 up- and 101 down-regulated genes after 7 days of treatment with lactate. The majority of the modulated genes are related to the expression of cytokines, transcription factors and cell-cycle- or cellular-matrix-associated proteins. In particular, lactate up-regulates the expression of interleukin-6 (3 days, 4.11-fold), of heat shock protein 70 (3 days, 2.36-fold) and of hypoxia-inducible factor-1alpha (3 days, 2.09-fold). A down-regulating effect of lactate is observed for superoxide dismutase 2 (1 h, 0.5-fold; 24 h, 0.4-fold; 7 days, 0.32-fold) and BCL2-associated X protein (24 h, 0.42-fold; 7 days, 0.4-fold). Expression of cell surface antigens clusters of differentiation 29, 44, 59, 73, 90, 105, 106 and 146 does not change over the time period of lactate treatment.
  
  
  CONCLUSIONS
  Lactate modulates expression of genes involved in wound healing. However, lactate does not profoundly change the phenotype of MSC. In addition to providing new insights into the wound healing physiology, these data could also be the rationale for new treatment strategies for chronic non-healing wounds.
authors.affiliation: Department of General and Transplant Surgery, University of Tuebingen, Tuebingen, Germany. derek.zieker@med.uni-tuebingen.de
authors.forename: Derek
authors.initials: D
authors.lastname: Zieker
authors.forename: Richard
authors.initials: R
authors.lastname: Schäfer
authors.forename: Jörg
authors.initials: J
authors.lastname: Glatzle
authors.forename: Kay
authors.initials: K
authors.lastname: Nieselt
authors.forename: Stephan
authors.initials: S
authors.lastname: Coerper
authors.forename: Torsten
authors.initials: T
authors.lastname: Kluba
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hunt
authors.forename: Stefan
authors.initials: S
authors.lastname: Beckert
mesh_terms: D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019344:Lactic Acid / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype
chemical_list: D019344:Lactic Acid