Role of transmembrane water exchange in glioma invasion/migration: in vivo preclinical study by relaxometry at very low magnetic field

Maria Rosaria Ruggiero, Hamza Ait-Itto, Simona Baroni, Sandra Pierre, Jean Boutonnat, Lionel Broche, Silvio Aime, Francois Berger, Simonnetta Geninatti Crich, Hana Lahrech

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This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions.
Original languageEnglish
Article number4180
Number of pages17
Issue number17
Early online date29 Aug 2022
Publication statusPublished - 1 Sept 2022

Bibliographical note

Funding: This project received funding from the European Union Horizon 2020 research and innovation program under grant agreement No 668119 (project IDentIFY). The Italian Ministry for Education and Research (MIUR) is gratefully acknowledged for yearly FOE funding to the EuroBioImaging Multi-Modal Molecular Imaging Italian Node (MMMI). Maria Rosaria Ruggiero was supported by an “FIRC-AIRC fellowship for Italy” and benefited from a COST Action grant (AC15209—EURELAX) to perform first IHC analysis at BrainTech Lab.
Acknowledgments: The authors thank the zootechnicians of the Clinatec animal facility led by Diane Agay for their assistance in animal management, and Reda Manyani, a master student, for his contribution to confirm IHC data analysis, first performed by the author Hamza Ait Itto.


  • glioma mouse model
  • glioma invasion
  • AQP4
  • AQP1
  • relaxometry
  • very low magnetic field
  • transmembrane water exchange


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