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Adenosine production in mesenchymal stromal cells in relation to their developmental status

Adenosinproduktion in mesenchymalen Stromazellen in Bezug auf deren Entwicklungsstatus

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Abstract

Background

Mesenchymal stromal cells (MSC) are multipotent progenitor cells found in the tumor microenvironment. They have an innate and regulatory immune activity, and they are able to produce immunosuppressive adenosine (ADO) via their ectonucleotidases CD39 and CD73. The present study explores ADO metabolism of MSC in relation to their developmental status.

Methods

We analyzed MSC (n = 6), chondrogenic progenitor cells (CPC, n = 8), and chondrocytes (n = 8) for surface markers by flow cytometry. The ability to hydrolyze ATP and to produce ADO was tested by luminescence assays and mass spectrometry.

Results

Significant differences in the surface marker expression of MSC, CPC, and chondrocytes were seen. While the expression of CD73 was observed to be the same on all cell types, the expression of the ectonucleotidase CD39 was significantly increased on MSC. Consequently, production of ADO was most abundant in MSC as compared with chondrocytes and CPC.

Conclusion

Mesenchymal stromal cells are potent producers of ADO and are, therefore, able to increase immunosuppression. As MSC differentiate into chondrocytes, they lose this ability and may take on other functions.

Zusammenfassung

Hintergrund

Mesenchymale Stromazellen (MSC) sind multipotente Vorläuferzellen, welche im Tumormikromilieu vorkommen. Sie besitzen eine angeborene und regulatorische Immunaktivität und können durch ihre Ektonukleotidasen CD39 und CD73 immunsuppressives Adenosin (ADO) produzieren. In der vorliegenden Studie wurde der ADO-Metabolismus von MSC in Bezug auf den Entwicklungsstatus der MSC untersucht.

Methoden

Dazu erfolgte eine durchflusszytometrische Untersuchung von MSC (n = 6), chondrogenen Vorläuferzellen (CPC, n = 8) und Chondrozyten (n = 8) in Bezug auf Oberflächenmarker. Die Fähigkeit, ATP zu hydrolysieren und ADO zu produzieren, wurde durch Lumineszenz-Assays und Massenspektrometrie getestet.

Ergebnisse

Signifikante Unterschiede in der Expression von Oberflächenmarkern wurden bei MSC, CPC und Chondrozyten festgestellt. Während die Expression von CD73 bei allen Zelltypen gleich war, erwies sich die Expression der Ektonukleotidase CD39 bei MSC als signifikant erhöht. Folglich war die Produktion von ADO bei MSC im Vergleich zu Chondrozyten und CPC am höchsten.

Schlussfolgerung

Mesenchymale Stromazellen sind potente Produzenten von ADO und können daher die Immunsuppression steigern. Wenn sich MSC in Chondrozyten differenzieren, verlieren sie diese Fähigkeit und können andere Funktionen übernehmen.

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Acknowledgements

We thank Katja Hasch, Gabriela Cudek, and Monika Jerg for their support in performing the experiments.

Funding

The research was supported by the German Research Foundation (DFG) Grant # SCHU 2536/3 (PJS), by NIH grants (EKJ) DK068575, DK079307, DK091190, HL109002, and by the International Graduate School in Molecular Medicine Ulm (SSJ).

Author information

Correspondence to P. J. Schuler M.D..

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Conflict of interest

S. S. Jeske, M. N. Theodoraki, E. Boelke, S. Laban, C. Brunner, N. Rotter, E. K. Jackson, T. K. Hoffmann, and P. J. Schuler declare that they have no competing interests.

All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Cartilage harvesting was approved by the local ethics committee (#152/08). Informed consent was obtained from all individual participants included in the study.

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Jeske, S.S., Theodoraki, M.N., Boelke, E. et al. Adenosine production in mesenchymal stromal cells in relation to their developmental status. HNO 68, 87–93 (2020). https://doi.org/10.1007/s00106-019-00805-z

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Keywords

  • Immunosuppression
  • Chondrogenic progenitor cells
  • Chondrocytes
  • Adenosine
  • Immunologic factors

Schlüsselwörter

  • Immunsuppression
  • Chondrogene Vorläuferzellen
  • Chondrozyten
  • Adenosin
  • Immunologische Faktoren