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Lactate modulates gene expression in human mesenchymal stem cells

  • Original Article
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Langenbeck's Archives of Surgery Aims and scope Submit manuscript

An Erratum to this article was published on 11 November 2008

Abstract

Purpose

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).

Materials and methods

MSC were isolated from human bone marrow using the density gradient technique and incubated with α-methoxyethoxymethyl containing 10% fetal calf serum at 37°C under 95% air and 5% CO2. 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-1α (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.

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References

  1. Hunt TK, Conolly WB, Aronson SB, Goldstein P (1978) Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds. Am J Surg 135(3):328–332

    Article  PubMed  CAS  Google Scholar 

  2. Hunt TK, Beckert S (2004) The theoretical and practical aspects of oxygen in wound healing. In: Lee, B. The wound management manual. pp 44–54

  3. Knighton DR, Silver IA, Hunt TK (1981) Regulation of wound-healing angiogenesis—effect of oxygen gradients and inspired oxygen concentration. Surgery 90(2):262–270

    PubMed  CAS  Google Scholar 

  4. Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, Roy S, Sen CK (2007) Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal 9(8):1115–1124

    Article  PubMed  CAS  Google Scholar 

  5. Gladden LB (2004) Lactate metabolism: a new paradigm for the third millenium. J Physiol 558(1):5–30

    Article  PubMed  CAS  Google Scholar 

  6. Ghani QP, Wagner S, Becker HD, Hunt TK, Hussain MZ (2004) Regulatory role of lactate in wound repair. Methods Enzymol 381:565–575

    Article  PubMed  CAS  Google Scholar 

  7. Constant JS, Feng JJ, Zabel DD, Yuan H, Suh DY, Scheuenstuhl H, Hunt TK, Hussain MZ (2000) Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair Regen 8(5):353–360

    Article  PubMed  CAS  Google Scholar 

  8. Trabold O, Wagner S, Wicke C, Scheuenstuhl H, Hussain MZ, Rosen N, Seremetiev A, Becker HD, Hunt TK (2003) Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen 11(6):504–509

    Article  PubMed  Google Scholar 

  9. Green H, Goldberg B (1964) Collagen and cell protein synthesis by established mammalian fibroblast line. Nature 204:347–349

    Article  PubMed  CAS  Google Scholar 

  10. Beckert S, Farrahi F, Aslam RS, Scheuenstuhl H, Konigsrainer A, Hussain MZ, Hunt TK (2006) Lactate stimulates endothelial cell migration. Wound Repair Regen 14(3):321–324

    Article  PubMed  Google Scholar 

  11. Aslam R, Beckert S, Scheuenstuhl H, Hussain MZ, Hunt TK (2005) High lactate in wounds may initiate vasculogenesis via stem cell homing. J Am Coll Surg 2001(3S):S58

    Article  Google Scholar 

  12. Cha J, Falanga V (2007) Stem cells in cutaneous wound healing. Clin Dermatol 25:73–78

    Article  PubMed  Google Scholar 

  13. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147

    Article  PubMed  CAS  Google Scholar 

  14. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci U S A 99(13):8932–8937

    Article  PubMed  CAS  Google Scholar 

  15. Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 100(14):8407–8411

    Article  PubMed  CAS  Google Scholar 

  16. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289(1):F31–42

    Article  PubMed  CAS  Google Scholar 

  17. Colter DC, Sekiya I, Prockop DJ (2001) Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A 98(14):7841–7845

    Article  PubMed  CAS  Google Scholar 

  18. Zieker D, Fehrenbach E, Dietzsch J, Fliegner J, Waidmann M, Nieselt K, Gebicke-Haerter P, Spanagel R, Simon P, Niess AM, Northoff H (2005) cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise. Physiol Genomics 23(3):287–294

    Article  PubMed  CAS  Google Scholar 

  19. Korbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, Champlin RE, Estrov Z (2002) Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 346(10):738–746

    Article  PubMed  Google Scholar 

  20. Fox JM, Chamberlain G, Ashton BA, Middleton J (2007) Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol 137(6):491–502

    Article  PubMed  CAS  Google Scholar 

  21. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11(4):367–368

    Article  PubMed  CAS  Google Scholar 

  22. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS, Dzau VJ (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20(6):661–669

    Article  PubMed  CAS  Google Scholar 

  23. Togel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C (2007) Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 292(5):F1626–1635

    Article  PubMed  CAS  Google Scholar 

  24. Mace KA, Yu DH, Paydar KZ, Boudreau N, Young DM (2007) Sustained expression of Hif-1alpha in the diabetic environment promotes angiogenesis and cutaneous wound repair. Wound Repair Regen 15(5):636–645

    Article  PubMed  Google Scholar 

  25. Kovalchin JT, Wang R, Wagh MS, Azoulay J, Sanders M, Chandawarkar RY (2006) In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis. Wound Repair Regen 14(2):129–137

    Article  PubMed  Google Scholar 

  26. Shroff EH, Snyder C, Chandel NS (2007) Bcl-2 family members regulate anoxia-induced cell death. Antioxid Redox Signal 9(9):1405–1409

    Article  PubMed  CAS  Google Scholar 

  27. Liu Q, Berchner-Pfannschmidt U, Moller U, Brecht M, Wotzlaw C, Acker H, Jungermann K, Kietzmann T (2004) A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression. Proc Natl Acad Sci U S A 101(12):4302–4307

    Article  PubMed  CAS  Google Scholar 

  28. Sen CK, Khanna S, Babior BM, Hunt TK, Ellison EC, Roy S (2002) Oxidant-induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J Biol Chem 277(36):33284–33290

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of General and Transplant Surgery, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany

    Derek Zieker, Jörg Glatzle, Stephan Coerper, Alfred Königsrainer & Stefan Beckert

  2. Department of Transfusion Medicine, University of Tuebingen, Tuebingen, Germany

    Richard Schäfer & Hinnak Northoff

  3. Center for Bioinformatics Tuebingen, Department of Information and Cognitive Sciences, University of Tuebingen, Tuebingen, Germany

    Kay Nieselt

  4. Department of Surgery, University of California, San Francisco, CA, USA

    Thomas K. Hunt

Authors
  1. Derek Zieker
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  2. Richard Schäfer
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  3. Jörg Glatzle
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  4. Kay Nieselt
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  6. Hinnak Northoff
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  8. Thomas K. Hunt
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  9. Stefan Beckert
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Corresponding author

Correspondence to Derek Zieker.

Additional information

German Society of Surgery, Surgical Forum 2008, Best of Abstracts.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00423-008-0430-3

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Zieker, D., Schäfer, R., Glatzle, J. et al. Lactate modulates gene expression in human mesenchymal stem cells. Langenbecks Arch Surg 393, 297–301 (2008). https://doi.org/10.1007/s00423-008-0286-6

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  • DOI: https://doi.org/10.1007/s00423-008-0286-6

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