<i>In vivo</i> spatiotemporal mapping of proliferation activity in gliomas via water-exchange dynamic contrast-enhanced MRI

Proliferation activity mapping is crucial for the guidance of first biopsy and treatment evaluation of gliomas due to the highly heterogenous nature of glioma tumor. Here we propose and demonstrate an ease-of-use way of <i>in vivo</i> spatiotemporal mapping of proliferation activity by simply tracking transmembrane water dynamics with magnetic resonance imaging (MRI). Specifically, we demonstrated that proliferation activity can accelerate the transmembrane water transport in glioma cells. <b>Method:</b> The transmembrane water-efflux rate (<i>k</i> _io) measured by water-exchange dynamic contrast-enhanced (DCE) MRI. Immunofluorescence, immunohistochemistry, and immunocytochemistry staining were used to validate results obtained from the <i>in vivo</i> imaging studies. <b>Results:</b> In glioma cell cultures, <i>k</i> _io precisely followed the dynamic changes of proliferation activity in growth cycles and response to temozolomide (TMZ) treatment. In both animal glioma model and human glioma, <i>k</i> _io linearly and strongly correlated with the spatial heterogeneity of intra-tumoral proliferation activity. More importantly, proliferation activity predicted by the single MRI parameter <i>k</i> _io is much more accurate than those predicted by state-of-the-art methods using multimodal standard MRIs and advanced machine learning. Upregulated aquaporin 4 (AQP4) expression were observed in most proliferating glioma cells and the knockout of AQP4 could largely slow down proliferation activity, suggesting AQP4 is the potential molecule connecting MRI-<i>k</i> _io with proliferation activity. <b>Conclusion</b>: This study provides an ease-of-use, accurate, and non-invasive imaging method for the spatiotemporal monitoring of proliferation activity in glioma.