Final Activity and Management Report Summary - MRI OF STEM CELLS (Molecular imaging of stem cell differentiation) Magnetic resonance (MR) contrast agents for non-invasive monitoring of cell migration and differentiation of stem and progenitor cells were developed during the course of the project. These contrast agents could be used to visualise the location and functional status of therapeutic cells that were engrafted into the brain or other organs. In contrast to currently used histological methods no removal of tissue was required. In other words, the cells could be monitored in the live host at repeated time points. Newly synthesised iron oxide particles, as well as chelated gadolinium (Gd) based magnetic resonance imaging (MRI) contrast agents, were used to label cells prior to their engraftment into the host. In these in vitro cell labelling studies, we selected those compounds that were: 1. highly sensitive for non-invasive visualisation using MRI, 2. that could be activated by either enzymes that were expressed by the targeted cell after their differentiation, activation or by transgenic cell lines and 3. that did not show any toxic or otherwise adverse effects on the normal cell biology. The synthesised Gd chelates were designed in such a way that they did not affect the MRI signal in their inactive state while they could be chemically modified by the targeted enzyme so that they contributed to a signal increase in the MR image. We addressed a variety of differentiation and activation processes as targets for such responsive contrast agents. For example, successful applications were the lipase based activation of the responsive contrast agent in the process of differentiation of progenitor cells into dendritic cells. Additional targets were enzymes expressed during the activation of dendritic cells, e.g. matrix metalloproteins, and during the differentiation of neural progenitor cells into neurons, such as glutamate decarboxylase. Those in vitro essays were evaluated for in vivo MR imaging in controls, stroke and brain tumours. As the concept was universally applicable for the visualisation of cell differentiation, it was anticipated to improve high resolution in vivo monitoring of cell function as well as to serve for models in other organs, other disease models and potentially cell replacement therapy in humans. Further development and application of those proof-of-principle studies would result in a non-invasive imaging method to monitor biomolecular reactions during disease progression and therapy.
