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Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation

Einfluss von Knochenmarks- oder mesenchymaler Stammzelltransplantation auf die orale Mukositis (Maus) bei fraktionierter Bestrahlung

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Abstract

Background and purpose

Oral mucositis is a severe and dose limiting early side effect of radiotherapy for head-and-neck tumors. This study was initiated to determine the effect of bone marrow- and mesenchymal stem cell transplantation on oral mucositis (mouse tongue model) induced by fractionated irradiation.

Material and methods

Daily fractionated irradiation (5 × 3 Gy/week) was given over 1 (days 0–4) or 3 weeks (days 0–4, 7–11, 14–18). Each protocol was terminated (day 7 or 21) by graded test doses (5 dose groups, 10 animals each) in order to generate complete dose–effect curves. The incidence of mucosal ulceration, corresponding to confluent mucositis grade 3 (RTOG/EORTC), was analyzed as the primary, clinically relevant endpoint. Bone marrow or mesenchymal stem cells were transplanted intravenously at various time points within these fractionation protocols.

Results

Transplantation of 6 × 106, but not of 3 × 106 bone marrow stem cells on day − 1, + 4, + 8, + 11 or + 15 significantly increased the ED50 values (dose, at which an ulcer is expected in 50 % of the mice); transplantation on day + 2, in contrast, was ineffective. Mesenchymal stem cell transplantation on day − 1, 2 or + 8 significantly, and on day + 4 marginally increased the ED50 values.

Conclusion

Transplantation of bone marrow or mesenchymal stem cells has the potential to modulate radiation-induced oral mucositis during fractionated radiotherapy. The effect is dependent on the timing of the transplantation. The mechanisms require further investigation.

Zusammenfassung

Hintergrund und Ziel

Die orale Mukositis ist eine schwere und dosislimitierende frühe Nebenwirkung der Strahlentherapie von Kopf-Hals-Tumoren. Ziel der vorliegenden Arbeit war die Untersuchung des Effekts der Transplantation von Knochenmarks- oder mesenchymalen Stammzellen auf die durch fraktionierte Bestrahlung induzierte orale Mukositis im Modell der Mäusezunge.

Material und Methoden

Die tägliche fraktionierte Bestrahlung (5-mal 3 Gy/Woche) wurde über eine (Tage 0–4) oder über 3 Wochen (Tage 0–4, 7–11, 14–18) appliziert. Abschließend erfolgte die lokale Bestrahlung (Tag 7 oder 21) in gestaffelten Testdosen (5 Dosisgruppen mit je 10 Tieren) zur Generierung kompletter Dosis-Effekt-Kurven. Die Inzidenz von Schleimhautulzera, entsprechend einer konfluenten Grad-3-Mukositis (RTOG/EORTC), wurde als primärer, klinisch relevanter Endpunkt analysiert. Knochenmark oder mesenchymale Stammzellen wurden zu verschiedenen Zeitpunkten während dieser Fraktionierungsprotokolle intravenös transplantiert.

Ergebnisse

Die Transplantation von 6 × 106, nicht jedoch von 3 × 106 Knochenmarkszellen, an den Tagen − 1, + 4, + 8, + 11 oder + 15 der fraktionierten Bestrahlung erhöhte die ED50-Werte (Dosis, bei der bei 50 % der Tiere ein Schleimhautulkus zu erwarten ist) signifikant; im Gegensatz dazu war die Transplantation an Tag + 2 wirkungslos. Die mesenchymale Stammzelltransplantation führte an den Tagen − 1, + 4 oder + 8 zu einer signifikanten und an Tag +4 zu einer marginalen Erhöhung der ED50-Werte.

Schlussfolgerung

Die Transplantation von Knochenmark bzw. mesenchymalen Stammzellen hat das Potential, die durch Strahlentherapie induzierte orale Mukositis zu beeinflussen. Dieser Effekt ist abhängig vom Zeitpunkt der Transplantation. Die Mechanismen bedürfen einer weiteren Abklärung.

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Acknowledgments

This project was supported by the European Commission; contract number LSHC-CT-2004-503436 (“FIRST”). The authors are grateful to Ms. D. Pfitzmann and the medical physicists of the Dept. of Radiotherapy and Radiation Oncology at the Medical Faculty Carl Gustav Carus of the Technical University Dresden for skillful assistance.

Compliance with ethical guidelines

Conflict of interest. M. Schmidt, J. Haagen, R. Noack, A. Siegemund, P. Gabriel, and W. Dörr state that there are no conflicts of interest. All national guidelines on the care and use of laboratory animals have been followed and the necessary approval was obtained from the relevant authorities.

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Authors and Affiliations

  1. Department of Radiotherapy and Radiation Oncology, OncoRay – National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, PF 50, 01307, Dresden, Germany

    M. Schmidt, J. Haagen, R. Noack, A. Siegemund, P. Gabriel & W. Dörr

  2. German Cancer Consortium (DKTK), Dresden, Germany

    M. Schmidt

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    M. Schmidt

  4. Dept. of Radiation Oncology/Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Comprehensive Cancer Center, Medical University/AKH Vienna, Vienna, Austria

    W. Dörr

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  1. M. Schmidt
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Correspondence to M. Schmidt.

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Schmidt, M., Haagen, J., Noack, R. et al. Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation. Strahlenther Onkol 190, 399–404 (2014). https://doi.org/10.1007/s00066-013-0510-3

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