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Mesenchymal stem cells in peripheral blood of severely injured patients

  • R. Wiegner
  • N.-E. Rudhart
  • E. Barth
  • F. Gebhard
  • L. Lampl
  • M. S. Huber-Lang
  • R. E. Brenner
Original Article
  • 237 Downloads

Abstract

Purpose

Mesenchymal stem cells (MSCs) are primarily stromal cells present in bone marrow and other tissues that are crucial for tissue regeneration and can be mobilized into peripheral blood after different types of organ damage. However, little is known about MSC appearance in blood in the setting of polytrauma.

Methods

We conducted a monocentered and longitudinal observational clinical study in 11 polytraumatized patients with an injury severity score (ISS) ≥ 24 to determine the numbers of MSCs in peripheral blood. Blood was collected from healthy volunteers and patients after polytrauma in the emergency room and 4, 12, 24, 48 h, 5 and 10 day later, and cells carrying MSC-surface markers (negative for CD45, positive for CD29, CD73, CD90, CD105, and CD166 in different combinations also employing the more stringent markers STRO1 and MSCA1) were detected and characterized using flow cytometry. Relative numbers of MSC-like cells were correlated with clinical parameters to evaluate if specific injury patterns had an influence on their presence in the blood cell pool.

Results

We were able to detect MSC marker-positive cells in both cohorts; however, the percentage of those cells present in the blood of patients during the first 10 day after injury was mostly similar to healthy volunteers, and significantly lowers starting at 4 h post trauma for one marker combination when compared to controls. Furthermore, the presence of a pelvis fracture was partly correlated with reduced relative numbers of MSC-like cells detectable in blood.

Conclusions

Polytrauma in humans was associated with partly reduced relative numbers of MSC-like cells detected in peripheral blood in the time course after injury. Further studies need to define if this reduction was due to lower mobilization from the bone marrow or to active migration to the sites of injury.

Keywords

Mesenchymal stem cells MSC-like cells Trauma Polytrauma Fracture 

Notes

Acknowledgements

This work was supported in part by a research grant from the German Ministry of Defense, Berlin, Germany (Vertragsforschungsvorhaben AZ E/U2AD/CD525/DF559).

Compliance with ethical standards

Conflict of interest

Rebecca Wiegner, Nina-Emily Hengartner, Eberhard Barth, Florian Gebhard, Lorenz Lampl, Markus S. Huber-Lang, and Rolf E. Brenner declare that they have no conflict of interest.

Statement of human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Haagsma JA, Graetz N, Bolliger I, Naghavi M, Higashi H, Mullany EC, et al. The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the global burden of disease study 2013. Inj Prev. 2016;22:3–18.CrossRefPubMedGoogle Scholar
  2. 2.
    Mokdad AH, Forouzanfar MH, Daoud F, Mokdad AA, El BC, Moradi-Lakeh M, et al. Global burden of diseases, injuries, and risk factors for young people’s health during 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2016;387:2383–401.CrossRefPubMedGoogle Scholar
  3. 3.
    Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, et al. Early complementopathy after multiple injuries in humans. Shock. 2012;37:348–54.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Fickert S, Fiedler J, Brenner RE. Identification of subpopulations with characteristics of mesenchymal progenitor cells from human osteoarthritic cartilage using triple staining for cell surface markers. Arthritis Res Ther. 2004;6:R422–32.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fickert S, Fiedler J, Brenner RE. Identification, quantification and isolation of mesenchymal progenitor cells from osteoarthritic synovium by fluorescence automated cell sorting. Osteoarthr Cartil. 2003;11:790–800.CrossRefPubMedGoogle Scholar
  8. 8.
    Klimczak A, Kozlowska U. Mesenchymal stromal cells and tissue-specific progenitor cells: their role in tissue homeostasis. Stem Cells Int. 2016;2016:4285215.CrossRefPubMedGoogle Scholar
  9. 9.
    Murray IR, West CC, Hardy WR, James AW, Park TS, Nguyen A, et al. Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci. 2014;71:1353–74.CrossRefPubMedGoogle Scholar
  10. 10.
    Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen. 2006;14:325–35.CrossRefPubMedGoogle Scholar
  11. 11.
    Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg. 2002;74:19–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Dominici M, Le BK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. Int Soc Cell Ther Pos Statement Cytother. 2006;8:315–7.Google Scholar
  13. 13.
    Huber-Lang M, Wiegner R, Lampl L, Brenner RE. Mesenchymal stem cells after polytrauma: actor and target. Stem Cells Int. 2016;2016:6289825.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hengartner NE, Fiedler J, Schrezenmeier H, Huber-Lang M, Brenner RE. Crucial role of IL1beta and C3a in the in vitro-response of multipotent mesenchymal stromal cells to inflammatory mediators of polytrauma. PLoS One. 2015;10:e0116772.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Granero-Molto F, Weis JA, Miga MI, Landis B, Myers TJ, O’Rear L, et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells. 2009;27:1887–98.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Li L, Jiang J. Regulatory factors of mesenchymal stem cell migration into injured tissues and their signal transduction mechanisms. Front Med. 2011;5:33–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA. 2003;100:8407–11.CrossRefPubMedGoogle Scholar
  18. 18.
    Gore AV, Bible LE, Song K, Livingston DH, Mohr AM, Sifri ZC. Mesenchymal stem cells increase T-regulatory cells and improve healing following trauma and hemorrhagic shock. J Trauma Acute Care Surg. 2015;79:48–52.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gore AV, Bible LE, Livingston DH, Mohr AM, Sifri ZC. Can mesenchymal stem cells reverse chronic stress-induced impairment of lung healing following traumatic injury? J Trauma Acute Care Surg. 2015;78:767–72.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hoogduijn MJ, Verstegen MM, Engela AU, Korevaar SS, Roemeling-van RM, Merino A, et al. No evidence for circulating mesenchymal stem cells in patients with organ injury. Stem Cells Dev. 2014;23:2328–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Seebach C, Henrich D, Tewksbury R, Wilhelm K, Marzi I. Number and proliferative capacity of human mesenchymal stem cells are modulated positively in multiple trauma patients and negatively in atrophic nonunions. Calcif Tissue Int. 2007;80:294–300.CrossRefPubMedGoogle Scholar
  22. 22.
    Alm JJ, Koivu HM, Heino TJ, Hentunen TA, Laitinen S, Aro HT. Circulating plastic adherent mesenchymal stem cells in aged hip fracture patients. J Orthop Res. 2010;28:1634–42.CrossRefPubMedGoogle Scholar
  23. 23.
    Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med. 2005;352:1959–66.CrossRefPubMedGoogle Scholar
  24. 24.
    He Q, Wan C, Li G. Concise review: multipotent mesenchymal stromal cells in blood. Stem Cells. 2007;25:69–77.CrossRefPubMedGoogle Scholar
  25. 25.
    Kuznetsov SA, Mankani MH, Gronthos S, Satomura K, Bianco P, Robey PG. Circulating skeletal stem cells. J Cell Biol. 2001;153:1133–40.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mansilla E, Marin GH, Drago H, Sturla F, Salas E, Gardiner C, et al. Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine. Transpl Proc. 2006;38:967–9.CrossRefGoogle Scholar
  27. 27.
    Ramirez M, Lucia A, Gomez-Gallego F, Esteve-Lanao J, Perez-Martinez A, Foster C, et al. Mobilisation of mesenchymal cells into blood in response to skeletal muscle injury. Br J Sports Med. 2006;40:719–22.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rochefort GY, Delorme B, Lopez A, Herault O, Bonnet P, Charbord P, et al. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells. 2006;24:2202–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Xu L, Li G. Circulating mesenchymal stem cells and their clinical implications. J Orthop Transl. 2014;2:1–7.Google Scholar
  30. 30.
    Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA, et al. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res. 2000;2:477–88.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Pignolo RJ, Kassem M. Circulating osteogenic cells: implications for injury, repair, and regeneration. J Bone Miner Res. 2011;26:1685–93.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang Y, Johnsen HE, Mortensen S, Bindslev L, Ripa RS, Haack-Sorensen M, et al. Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention. Heart. 2006;92:768–74.CrossRefPubMedGoogle Scholar
  33. 33.
    Gebhard F, Huber-Lang M. Polytrauma–pathophysiology and management principles. Langenbecks Arch Surg. 2008;393:825–31.CrossRefPubMedGoogle Scholar
  34. 34.
    Bernardo ME, Locatelli F, Fibbe WE. Mesenchymal stromal cells. Ann N Y Acad Sci. 2009;1176:101–17.CrossRefPubMedGoogle Scholar
  35. 35.
    Simmons PJ, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 1991;78:55–62.PubMedGoogle Scholar
  36. 36.
    Kim YH, Yoon DS, Kim HO, Lee JW. Characterization of different subpopulations from bone marrow-derived mesenchymal stromal cells by alkaline phosphatase expression. Stem Cells Dev. 2012;21:2958–68.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32:1408–19.CrossRefPubMedGoogle Scholar
  38. 38.
    Marlicz W, Zuba-Surma E, Kucia M, Blogowski W, Starzynska T, Ratajczak MZ. Various types of stem cells, including a population of very small embryonic-like stem cells, are mobilized into peripheral blood in patients with Crohn’s disease. Inflamm Bowel Dis. 2012;18:1711–22.CrossRefPubMedGoogle Scholar
  39. 39.
    Starzynska T, Dabkowski K, Blogowski W, Zuba-Surma E, Budkowska M, Salata D, et al. An intensified systemic trafficking of bone marrow-derived stem/progenitor cells in patients with pancreatic cancer. J Cell Mol Med. 2013;17:792–9.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Blogowski W, Zuba-Surma E, Salata D, Budkowska M, Dolegowska B, Starzynska T. Peripheral trafficking of bone-marrow-derived stem cells in patients with different types of gastric neoplasms. Oncoimmunology. 2016;5:e1099798.CrossRefPubMedGoogle Scholar
  41. 41.
    Ferensztajn-Rochowiak E, Kucharska-Mazur J, Samochowiec J, Ratajczak MZ, Michalak M, Rybakowski JK. The effect of long-term lithium treatment of bipolar disorder on stem cells circulating in peripheral blood. World J Biol Psychiatry 2017;18(1):54–62.CrossRefPubMedGoogle Scholar
  42. 42.
    Marketou ME, Parthenakis FI, Kalyva A, Pontikoglou C, Maragkoudakis S, Kontaraki JE, et al. Increased mobilization of mesenchymal stem cells in patients with essential hypertension: the effect of left ventricular hypertrophy. J Clin Hypertens (Greenwich). 2014;16:883–8.CrossRefGoogle Scholar
  43. 43.
    Marketou ME, Parthenakis FI, Kalyva A, Pontikoglou C, Maragkoudakis S, Kontaraki JE, et al. Circulating mesenchymal stem cells in patients with hypertrophic cardiomyopathy. Cardiovasc Pathol. 2015;24:149–53.CrossRefPubMedGoogle Scholar
  44. 44.
    Sielatycka K, Poniewierska-Baran A, Nurek K, Torbe A, Ratajczak MZ. Novel view on umbilical cord blood and maternal peripheral blood-an evidence for an increase in the number of circulating stem cells on both sides of the fetal-maternal circulation barrier. Stem Cell Rev. 2017. doi: 10.1007/s12015-017-9763-z.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25:2739–49.CrossRefPubMedGoogle Scholar
  46. 46.
    Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Naaldijk Y, Johnson AA, Ishak S, Meisel HJ, Hohaus C, Stolzing A. Migrational changes of mesenchymal stem cells in response to cytokines, growth factors, hypoxia, and aging. Exp Cell Res. 2015;338:97–104.CrossRefPubMedGoogle Scholar
  48. 48.
    Hocking AM. The role of chemokines in mesenchymal stem cell homing to wounds. Adv Wound Care (New Rochelle). 2015;4:623–30.CrossRefGoogle Scholar
  49. 49.
    Gebhard F, Pfetsch H, Steinbach G, Strecker W, Kinzl L, Bruckner UB. Is interleukin 6 an early marker of injury severity following major trauma in humans? Arch Surg. 2000;135:291–5.CrossRefPubMedGoogle Scholar
  50. 50.
    von BR, Oikonomou, Sulaj D, Mohammed A, Hotz-Wagenblatt S, Grone A. HJ et al.: CD166/ALCAM mediates proinflammatory effects of S100B in delayed type hypersensitivity. J Immunol. 2013;191:369–77.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Esteve D, Galitzky J, Bouloumie A, Fonta C, Buchet R, Magne D. Multiple functions of MSCA-1/TNAP in adult mesenchymal progenitor/stromal cells. Stem Cells Int. 2016;2016:1815982.CrossRefPubMedGoogle Scholar
  52. 52.
    Antonioli L, Pacher P, Vizi ES, Hasko G. CD39 and CD73 in immunity and inflammation. Trends Mol Med. 2013;19:355–67.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7:e2062.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • R. Wiegner
    • 1
  • N.-E. Rudhart
    • 2
  • E. Barth
    • 3
  • F. Gebhard
    • 4
  • L. Lampl
    • 5
  • M. S. Huber-Lang
    • 1
  • R. E. Brenner
    • 2
  1. 1.Institute of Clinical and Experimental Trauma ImmunologyUniversity Hospital UlmUlmGermany
  2. 2.Department of Orthopedics, Division for Biochemistry of Joint and Connective Tissue DiseasesUniversity of UlmUlmGermany
  3. 3.Department of AnesthesiologyUniversity Hospital of UlmUlmGermany
  4. 4.Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive SurgeryUniversity Hospital of UlmUlmGermany
  5. 5.Department of AnesthesiologyMilitary Hospital UlmUlmGermany

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