Monitoring stem cell migration in the nervous system by in vivo magnetic resonance imaging

Abstract

The fast growing understanding in stem cell biology has led to the exploration of the therapeutic potential of endogenous or implanted stem cells as a cell replacement therapy for stroke. Arvidsson et al. 1 demonstrated a significant activation of neurogenesis in the subventricular zone of ischemic rats while Helen Hodges 2 reported on migration of implanted embryonic stem cells towards the lesion periphery in ischemic rats, followed by outcome improvements relative to animals without cell implantations. These studies depended on established invasive techniques requiring the sacrifice of large groups of animals to investigate the temporal profiles of dynamical parameters such as migrational activity or cell differentiation in response to either cerebral lesion or (patho-)physiological factors. It is therefore highly desirable to exploit a noninvasive imaging technique such as MRI to observe (implanted) stem cells in a longitudinal study. A few laboratories 3, 4 have begun to label stem cells with MRI contrast agents, preferably ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) to detect the cells with strong contrast against the background tissue of the host organ. Optimizing the MRI scanner hardware and the complete in vivo protocol we have recently succeeded in performing ultra-high MR imaging with isotropic resolution of 78m, at an experimental time of only less than 70 min, thus making a longitudinal study with repetitive anesthesia sessions easily tolerable even for lesioned animals 5. The USPIO-induced hypointensity of the stem cells however leads to various situations making an unambiguous assignment for the contrast to the cells difficult. We have found that under ischemic conditions, a rather delayed vascular degradation leads to iron uptake by macrophages in the vicinity of the leaky vessels, thus producing an image contrast closely similar to that of stem cells spread out over the periphery of an ischemic lesion 6. Further, strategies will be discussed to distinguish hypointense contrast of vascular origin (BOLD effect) from that of stem cells by exploiting physiological modulation of the signal intensity and contrast mechanisms 7. Finally, new labeling strategies will be presented in an effort to avoid the confounding factors of the USPIO induced hypointensity and explore the potential of a new generation of MR contrast agents: Gd based chelates which can be used as nezyme activity or gene expression reporters. The presentation will discuss the potential and challenges of stem cell monitoring in the intact organism using highly resolved MR imaging. Particular focus will be given to cells implanted into rat or mouse brain. Chances for future applications of imaging not only localization of implanted cells but also their functional status (e.g. migration; differentiation; transformation) will be presented.