Can exogenous stem cells improve outcome after experimental stroke? The challenge of combined MRI imaging of stem cell dynamics, cell differentiation and functional outcome

Abstract

Conventional therapies of stroke have so far demonstrated limited success. Cerebroprotective drugs have been extensi-vely and rather successfully investigated in animal experiments. In the clinical environment, however, all drugs have failed so far. Throm-bo-lysis is the only strategy with successful translation from experimental into clinical neurology. Experimental and clinical research on thrombolysis of stroke has extensively documented that it will prevent further expansion of the ischemic lesion by stabilizing the penumbral tissue but it will not reverse the damage of the early irreversibly damaged ischemic core area. The recent breath-taking developments in stem cell biology have motivated the evaluation of the therapeutic potential of endogenous or implan-ted 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 the lab of Helen Hodges 2 reported on migration of implanted ES cells towards the lesion periphery in ischemic rats, followed by outcome improve-ments relative to animals without cell implantations. Using fMRI two groups investigated the sponta-neous functional improvement and activation potential of the somatosensory cortex of rats following induction of stroke reporting a transient re-organization process, during which the representation area was shifted to the contralateral, undamaged hemisphere during a transition period 3, 4. While some investigators looked at histological evolution of the lesion after treatment with stem cell implantation, no study focussed on the mechanisms of behavior improvements in these treated situations: restitution of function of the original repre-sen-tation area or plasticity dependent re-organization, enhanced by the stem cell inter-action with the host organ. Such investigations present an enormous challenge on the design and execution of a complex experimental protocol. On the one hand, the evolution of the lesion must be characterized in parallel with the fate of the implanted stem cells (migrational dynamics to the target zone; cell specific differentiation). On the other hand, a potential therapeutical success must be evaluated in its temporal development. Finally, mechanisms explaining a potential outcome improvement are of great interest. Most recent investigations are exploring the potential contribution of molecular imaging techniques and have reported the in vivo monitoring of stem cell migration in rat 5 and mouse brain after stroke 6. The present contribution will demonstrate the possibilities (and limits) of non-invasive imaging modalities for the characterization of the lesion and the (implanted) cell mobility, while the functional fate (e.g. differentiation status) is described by way of immuno-histochemistry. Parallel investigations on the functional deficit and outcome improvement, respectively, are presented. Mechanisms responsible for a functional improvement (statial reorganization vs recovery of primary representation field) can be studied by longitudinal fMRI studies of anesthetized animals, allowing the localization of activated brain areas.