Monitoring Stem Cell Therapy in Vivo Using Magnetodendrimers as a New Class of Cellular MR Contrast Agents

Abstract

Human embryonic stem (ES) and germ (EG) cells have been isolated and can now be propagated indefinitely in culture (1,2). They can be differentiated into most, if not all cell types, and offer unprecedented therapeutic potential to replace or substitute defunct endogenous cell populations. In order to track the biodistribution of transplanted cells in animals, including their migration in vivo, cells can be given a tag before grafting. These tags currently include fluorescent labels, thymidine analogues, and transfected reporter genes (e.g. LacZ or GFP), which can be visualized using (immuno)histochemical procedures following tissue removal at a particular given time point. The clinical use of progenitor and stem cells in humans, however, will require a technique that can monitor their fate non-invasively and repeatedly, in order to take a momentary “snapshot” assessment of the cellular biodistribution at a particular given time point. As a result, magnetic resonance (MR) tracking of magnetically labeled stem and progenitor cells is now emerging as a new technology (3,4). A further implementation of this potentially powerful technique will greatly benefit from the availability of magnetic probes that can render cells highly magnetic during their normal expansion in culture (5). We present here magnetodendrimers (MD-100) as a new class of magnetic probes that can achieve a high degree of intracellular magnetic labeling for virtually any cell type, including human mesenchymal and neural stem cells (NSCs). Our rationale to use dendrimers as the iron oxide-associated polymer is based upon its reported high efficiency to shuttle other macromolecules such as oligonucleotides across cell membranes (7). Analogous to the use of dendrimers as transfection agents (including the commercially available agents SuperfectTM and PolyfectTM), a key feature of magnetodendrimers is its universal applicability for the magnetic labeling of cells, that is, the cellular uptake is non-specific and not dependent on binding to membrane receptors. Using a rat brain transplantation model, we show here that NSC-derived, MD100-labeled oligodendroglial progenitors can be readily detected in vivo following transplantation, with an excellent correlation between the obtained MR contrast and staining for (LacZ) transfected -galactosidase.