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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Collaborative Specialization

Molecular Imaging

Supervisor

Foster, Paula J.

Abstract

Cell therapies, including mesenchymal stem cells (MSC) and regulatory T cells (Tregs) have shown potent and long-lasting therapeutic benefit in several disease applications. Unfortunately, the effectiveness of these therapies is variable and following administration, it is largely unknown where therapeutic cells traffic and how many persist over time. This thesis aims to advance and compare iron- and fluorine-19 (19F)-based magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) for therapeutic cell tracking.

First, we developed a trimodal imaging approach to study MSC fate in vivo. In a mouse model, iron-labeled MSC were detected by MRI and MPI, and each modality provided unique information on MSC quantity (MPI) and anatomical localization (MPI) in vivo. In these same mice, 19F MRI was used to assess inflammatory influx to the injection site after intravenous administration of 19F-perfluorocarbon agent. Next, the sensitivity and cellular detection limits of 19F MRI were compared to MPI. MPI showed superior sensitivity, as fewer iron-labeled cells could be detected with MPI (4000 MSCs) compared to 19F-labeled cells with 19F MRI (256,000 MSCs) using the same imaging time. For cell tracking, estimation of cell number is critical, so we sought to develop and test four methods to select and quantify MPI signal from an image. In this project, it is demonstrated that while MPI signal scales directly linear with the amount of iron present, 3 users showed more accurate and precise quantification when they considered a larger area for each signal in the image. In the final chapter, we demonstrate a clinically-applicable 19F MRI imaging approach for tracking in vivo biodistribution of Tregs. This approach involved a dual tuned MRI surface coil with sensitive bSSFP imaging sequence on a 3 Tesla human MRI. The ability to non-invasively quantify and image injected cells in vivo with high sensitivity will improve the efficacy and safety of cell therapy.

Summary for Lay Audience

Cell therapy is a new treatment for many diseases and works by using stem cells or immune cells. These cells can be grown and modified in a lab so that there are enough cells with the right function that can be given to a patient. Although very promising, there are many questions remaining that can only be answered using imaging, such as where do cells go after implanted? how long do they last? how many are there? There are four projects in this thesis where we use imaging methods to answer these questions: magnetic resonance imaging (MRI), fluorine-19 (19F) MRI, and magnetic particle imaging (MPI). For these imaging modalities to work, cells must be labeled with an imaging agent, either iron or 19F. First, we used all these methods in combination to study stem cells after injection to mice and the immune response that happens after the injection. Each imaging method gives us new information about stem cells; MRI shows the injection site, MPI measures how many stem cells are present over time, and 19F MRI measures the immune response. Combining 3 modalities gives us a full picture to understand what is happening to stem cells after they are administered. It is also important to understand the limitations of these imaging methods. We found that MPI could detect fewer cells compared to 19F MRI and this is considered an advantage. MPI is a newer imaging modality and in many publications it was unclear how to measure imaging signals. We created and compared four methods to see which gave the most accurate measurement with minor differences between the person who measures it. Finally, it is important that the imaging technique could be used for humans, not just mice. In the last project we label immune cells called regulatory T cells with 19F and image these cells using a human MRI. With 19F MRI we can see where these T cells migrate in mice and measure the number of cells at each location. We are confident that these imaging methods will help to better understand and monitor cell therapies in patients.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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