In Vivo Imaging for the Detection and Quantitation of Transplanted Stem/Progenitor Cells in Nonhuman Primates
Stem cells hold great potential for treating a variety of human diseases, but more information is needed on how they will function once administered to patients for regenerative medicine purposes. If imaging techniques can be developed that allow the monitoring of these transplanted stem and progenitor cells over time once injected into the body, this would provide a very powerful tool to determine the fate of the cells. This proposal specifically addresses new ways to optimize the use of positron emission tomography (PET), an imaging technology currently used in the human clinical setting, for this purpose. PET is an imaging technique that produces a three-dimensional image by detection of a tracer or label that has been introduced into the body. In these studies we plan to optimize these imaging techniques when a special tag or label is attached to individual stem and progenitor cells, and address the sensitivity of the scanner for their detection. An important goal is to improve the ability to detect the small quantities of cells that may be used, and ensure that the images obtained can accurately identify the number of cells at any given location. Several factors limit the ability to detect the cells reliably in current PET scanners. These limitations include an inherent background signal which alters the ability to accurately identify the cells injected. In addition, processing of the information obtained by the PET imaging system has not been optimized for monitoring transplanted cells where the cell quantity may be very small and the tag or label used to find the cells may be difficult to detect. Further, the methods used to place the tag or label on the cells needs to balance the requirements for obtaining good imaging information without damaging the cells or altering their capabilities in the labeling process. Our plan is to investigate these crucial issues and current roadblocks in the context of stem cell imaging with the goal of substantially advancing the imaging field for stem cell therapies. We will use model systems to ensure that the techniques and applications developed and proposed for human use are safe and do not cause harm to patients of all age groups. These studies will focus on optimizing PET imaging techniques for cell quantification and identification, and develop and refine new ways to monitor cells, including those differentiated from human embryonic stem cells, for short and extended periods of time.
This proposal meets the objective of CIRM RFA 08-02 by providing new ways to overcome current gaps and roadblocks for sensitive imaging methods that would allow the detection of stem and progenitor cells administered to patients for regenerative medicine purposes. These new tools and technologies will serve the State of California and its citizens by providing reliable techniques for any scientist or physician to assess their ideas and new cell transplant protocols before considering use in human patients. Once tested and shown to be effective, these same imaging techniques can then be used in human patients. While stem cells, particularly human embryonic stem cells, have tremendous potential for treating a variety of human diseases, many questions remain about their safety and outcome once they are used. If imaging techniques can be developed that allows the monitoring of the cells over time, this would provide a very powerful tool to determine the fate of the cells after injection into patients. The results of these studies will fill a critical need and substantially advance the regenerative medicine field for a host of human diseases for which there are currently few therapeutic options.
Stem cells hold great potential for treating a variety of human diseases, but more information is needed on how they will function once administered to patients for regenerative medicine purposes. Our studies are focused on addressing new ways to optimize the use of positron emission tomography (PET), an imaging technology used in the human clinical setting, to monitor stem and progenitor cells post-transplantation. In our studies we have accomplished our stated milestones and optimized PET imaging techniques by addressing the sensitivity of the scanner and ways to improve the detection of small quantities of transplanted cells. We have also carefully identified methods for safely placing imaging labels on the cells without altering the proliferative and growth potential of the cells under investigation. We are now poised to use our model systems to test how these improvements enhance our established imaging protocols.
Imaging methods to monitor stem and progenitor cells post-transplant are needed to assess engrafted cells once injected into the body and over time. These studies are addressing the refinements needed in PET imaging equipment to effectively locate the cells, and ways to safely label the cells without altering their capabilities and functions in a preclinical setting.
Noninvasive imaging systems include a wide range of technologies that make use of different contrast mechanisms to provide images that can reflect anatomy, physiology, metabolism, and more specifically interactions with proteins, gene expression, or to track therapeutic molecules and transplanted stem and progenitor cells. While in vivo imaging technologies are clearly essential for the development of new stem cell therapies for humans, imaging techniques with sufficient sensitivity to detect small quantities of cells are needed to monitor and evaluate safety and efficiency of new stem cell therapies for a spectrum of human diseases. Nuclear medicine techniques, especially positron emission tomography (PET), have much higher sensitivity than other imaging modalities and can provide 3D quantitative images. Outcomes using PET imaging can also be translated from animal models to humans. These studies focused on two overriding objectives: to assess current PET imaging systems with the goal of understanding and improving detection and quantification of stem cells transplanted in vivo; and to develop methods to radiolabel stem and progenitor cells for transplant and short-term tracking in vivo with PET. These studies have shown that some commercial PET scanners are not as sensitive as others for imaging low-activity sources produced by labeled cells because of inherent background noise that confounds PET imaging. In addition, new methods for labeling cells in vitro and in vivo have been developed that will aid in identifying engrafted stem/progenitor cells using PET post-transplantation.