For cell replacement therapy to be broadly applied to regenerative strategies will require that several obstacles be overcome. Amongthese is having the ability to non-invasively monitor in real-time the engraftment and migration of transplanted cells. To help overcome this obstacle, an MRI Imaging Core will be established to develop and provide non-invasive, real-time cell imaging that can be used to assess the viability and differentiation of transplanted human embryonic stem cells (hESCs) in the living mouse post- transplant. For this Core, we will develop multimodal contrast agents and probes for the in vivo imaging of transplanted stem cells. The term multimodal is defined as a contrast agent that can be simultaneously detected by more then one imaging modality. These new contrast agents will be designed to be detected by both magnetic resonance imaging (MRI) and optical imaging so that the unique advantages of both techniques can be exploited (co-registration of acquired data).
The specific aims for this Core are as follows. (1) To synthesize T1 magnetic resonance contrast agents coupled to an optical probe. To permit co- registration of acquired image data, probes with a fluorescent and a MR probe will be synthesized. We will synthesize large and small molecular weight species. Several fluorescent dyes including fluorescein, Oregon Green 488, tetramethylrhodamine, pyrene, Alexa Fluor 568, and Texas Red will be covalently attached to dextran and lysine polymers that are multiply labeled with gadalinium chelates. (2) To prepare T2 magnetic resonance contrast agents coupled to an optical probe. The development of multimodal T2 contrast agents with a superparamagnetic iron oxide core and a covalently attached fluorescent dye will be prepared to acquire light and MRI microscopy data employing a T2 probe in place of a T1 probe. T2 probes are more sensitive then T1 agents. This factor may be required for long-term fate analysis of stem cell engraftment and migration. (3) To develop delivery vehicles for multimodal probes. The goal of this aim is to develop efficient means of in vivo delivery for the multimodal contrast agents described in Specific Aims 1 and 2. Frequently, probes that are charged, and of high molecularweight, do not cross cell membranes. We will design, synthesize and test small-molecule delivery vehicles capable of crossing cell membranes in vivo. (4) To test the in vitro and in vivo effectiveness of the new multimodal agents. Current assays of stem cell engraftment and viability do not permit the in vivo evaluation of the graft. In this Aim, we will test, in direct collaboration with the investigators on the different projects, the toxicity, permeability and image enhancement (over time) of labeled, transplanted stem cells. This will allow noninvasive, real-time imaging of transplanted hESCs. Thus; this Core will develop and provide a novel but critical technology needed to translate hESC research into new therapies.
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